Cyclic urea derivatives, pharmaceutical compositions containing these compounds and processes for preparing them

ABSTRACT

The invention relates to cyclic urea derivatives of general formula I ##STR1## wherein R a , R b , X and Y are defined as in claim 1, the tautomers, stereoisomers and salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, which have valuable pharmacological properties, preferably aggregation inhibiting effects, and to drugs containing the compounds and processes for preparing them.

This is a division of application Ser. No. 08/120,008, filed Sep. 10,1993 now U.S. Pat. No. 5,681,841.

The invention relates to cyclic urea derivatives of general formula##STR2## the tautomers and stereoisomers and the salts thereof,particularly the physiologically acceptable salts thereof with inorganicor organic acids or bases, which have, inter alia, valuablepharmacological properties, preferably aggregation-inhibiting effects,

with the exception of

1-(4-amidino-phenyl)-3-4-(2-carboxy-ethyl)-cyclohexyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-methoxycarbonyl-ethyl)-cyclohexyl!-imidazolidin-2-one,

1-(4-cyano-phenyl)-3-4-(2-methoxycarbonyl-ethyl)-cyclohexyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3- 4-2-(5-tetrazolyl)-ethyl!-phenyl!-imidazolidin-2-one,

1-(4-aminomethyl-cyclohexyl)-3-4-(2-carboxy-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-aminomethyl-cyclohexyl)-3-4-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-3-phenyl-3H-imidazol-2-one,

4-(4'-amidino-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3-phenyl-3H-imidazol-2-one,

4-(4'-cyano-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3-phenyl-3H-imidazol-2-one,

4-4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-3-phenyl-imidazolidin-2-one

4-(4'-amidino-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3-phenyl-imidazolidin-2-one,

1-(4'-amidino-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-3H-imidazol-2-one,

1-(4'-cyano-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-3H-imidazol-2-one,

1-(4'-amidino-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-imidazolidin-2,4-dione,

1-(4'-cyano-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-imidazolidin-2,4-dione

1-(4'-amidino-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-3,4,5,6-tetrahydro-1H-pyrimidin-2-one,

1-(4'-cyano-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-3,4,5,6-tetrahydro-1H-pyrimidin-2-one,

2-(4-amidino-phenyl)-4-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

4-4-(2-Isopropyloxycarbonyl-ethyl)-phenyl!-2-(4-methoxy-carbonylamidino-phenyl)-5-methyl-4H-1,2,4-triazol-3-one,

1-(4-amidino-phenyl)-3-4-(2-ethoxycarbonyl-ethyl)-phenyl!-3H-imidazol-2-one,

1-(4-ethoxycarbonylamidino-phenyl)-3-4-(2-ethoxycarbonyl-ethyl)-phenyl!-3H-imidazol-2-one,

1-(4-ethoxycarbonylamidino-phenyl)-3-4-(2-ethoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-methoxycarbonylamidino-phenyl)-3-4-(2-methoxycarbonyl-ethyl)-cyclohexyl!-imidazolidin-2-one,

4-4-(2-isobutyloxycarbonyl-ethyl)-phenyl!-2-(4-methoxy-carbonylamidino-phenyl)-5-methyl-4H-1,2,4-triazol-3-one,

2-(4-amidino-phenyl)-4-4-(2-isobutyloxycarbonyl-ethyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

1-(1-amino-5-indanyl)-3- 4-(2-carboxy-ethyl)-phenyl!-imidazolidin-2-one,

1-(1-amino-5-indanyl)-3-4-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

2-(4-amidino-phenyl)-5-ethyl-4-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-4H-1,2,4-triazol-3-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-4-methyl-3H-imidazol-2-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-3H-imidazol-2-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-imidazolidin-2,4-dione,

2-(4-amidino-phenyl)-4-4-(2-carboxy-ethyl)-phenyl!-5-trifluoromethyl-4H-1,2,4-triazol-3-one and

3-(4-cyano-phenyl)-1-(4-ethoxycarbonyl-butyl)-3H-imidazo-4,5-b!pyridin-2-one,

pharmaceutical compositions containing these compounds, the use thereofand processes for preparing them.

In general formula I above, with the proviso that at least one ofconditions (i) to (ix) below must be satisfied

(i) X denotes a carbimino group substituted by a cyano group at thenitrogen atom, or a 1-nitro-ethen-2,2-diyl or 1,1-dicyano-ethen-2,2-diylgroup,

(ii) Y denotes a C₅₋₇ -1,2-cycloalkylene group optionally substituted byR_(c) or R_(d) or by R_(c) and R_(d),

(iii) A denotes a C₁₋₅ -aminoalkyl group or an amino, amidino orguanidino group, in which, at one of the nitrogen atoms in each of theabove mentioned groups, a hydrogen atom is replaced by an R₁--CO--O--(R₂ CR₃)--O--CO-- group,

(iv) B denotes a C₃₋₇ -cycloalkylene group optionally substituted by oneor two alkyl groups,

a C₄₋₅ -cycloalkylene group optionally substituted by a group R_(c) andwhich may additionally be substituted by 1 to 4 alkyl groups, and inwhich, in the cycloalkylene moiety, a >CH unit is replaced by a nitrogenatom,

a C₆₋₈ -cycloalkylene group optionally substituted by a group R_(c) andwhich may additionally be substituted by 1 to 4 alkyl groups and inwhich, in the cycloalkylene moiety, a >CH unit is replaced by a nitrogenatom and additionally another >CH unit in the 4-position may be replacedby a nitrogen atom, whilst, moreover, in the above mentioned 6-8membered rings one or two methylene groups adjacent to a nitrogen atommay each be replaced by a carbonyl group,

a C₅₋₇ -cycloalkenylene group optionally substituted by 1 or 2 alkylgroups and which may additionally be substituted by 1 or 2 methyl groupsand wherein, in the cycloalkenylene moiety, a >CH unit is replaced by anitrogen atom,

a C₅₋₇ -cycloalkylene group, wherein a >CH unit is replaced by anitrogen atom which is attached to Group A, and in which two hydrogenatoms on the carbon skeleton are replaced by a straight-chained alkylenebridge, this bridge containing 2 to 6 carbon atoms if it replaces twohydrogen atoms on the same carbon atom or containing 1 to 5 carbon atomsif it replaces two hydrogen atoms on adjacent carbon atoms, orcontaining 1 to 4 carbon atoms if it replaces two hydrogen atoms oncarbon atoms which are separated by a further atom, or containing 1 to 3carbon atoms if it replaces two hydrogen atoms on carbon atoms which areseparated by 2 further atoms, whilst the above groups may each besubstituted by 1 or 2 alkyl groups,

a C₁₋₆ -alkylene group linked to the group C via a group W,

or B together with A denotes a pyridyl group optionally substituted byone or two alkyl groups, or a piperidinyl group in which the hydrogenatom in the 1-position together with a hydrogen atom in the 2-positionis replaced by a straight-chained C₃₋₄ -alkylene group, or B togetherwith A denotes a piperidinyl group in which the hydrogen atoms in the1-position and the 3-position are replaced by a straight-chained C₂₋₄-alkylene group, or a piperidinyl group in which the hydrogen atom inthe 1-position and a hydrogen atom in the 4-position are replaced by astraight-chained C₁₋₃ -alkylene group, whilst the methylene group of anethylene chain attached to the 4-position may be replaced by ahydroxymethylene or carbonyl group and additionally the nitrogen atom ofthese above mentioned bicyclic groups, which may be substituted in thecarbon skeleton by 1 or 2 alkyl groups, may be completed by borane orquaternised by a benzyl group optionally substituted by one to twomethoxy groups in the phenyl nucleus,

(v) C denotes a C₁₋₆ -alkylene group in which a methylene group isreplaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl or NRgroup or wherein an ethylene group is replaced by a CONR₅ or NR₅ COgroup,

a 3-7-membered cycloalkylene group optionally substituted by one or twoalkyl groups,

a cyclohexylene group in which two carbon atoms separated by 3 bonds mayadditionally be linked by a straight-chained C₁₋₃ -alkylene group, andthese bicyclic groups may also be substituted by one to two alkylgroups,

an indanylene, naphthylene, 1,2,3,4-tetrahydronaphthylene orbenzosuberanylene group, wherein the saturated rings may each besubstituted by one or two alkyl groups and the aromatic rings may eachbe substituted by a fluorine, chlorine, bromine or iodine atom, or by analkyl, trifluoromethyl, hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl,alkysulphonyl or qyano group and wherein additionally, one or twomethine groups may each be replaced by a nitrogen atom,

a C₄₋₅ -cycloalkylene group optionally substituted by the group R_(c),and optionally additionally. substituted by 1 to 4 alkyl groups andwherein in the cycloalkylene moiety a >CH unit is replaced by a nitrogenatom,

a C₆₋₈ -cycloalkylene group optionally substituted by the group R_(c)and which may additionally be substituted by 1 to 4 alkyl groups andwherein, in the cycloalkylene moiety, a >CH unit is replaced by anitrogen atom and additionally another >CH unit located in the4-position may be replaced by a nitrogen atom, whilst moreover in theabove mentioned 6-8-membered rings one or two methylene groups adjacentto a nitrogen atom may each be replaced by a carbonyl group,

a C₅₋₇ -cycloalkenylene group optionally substituted by one or two alkylgroups and which may additionally be substituted by one or two methylgroups and wherein, in the cycloalkenylene moiety a >CH unit is replacedby a nitrogen atom,

a C₅₋₇ -cycloalkylene group wherein a >CH unit is replaced by a nitrogenatom which is attached to group A and wherein additionally two hydrogenatoms on the carbon skeleton are replaced by a straight-chained alkylenebridge, this bridge containing two to six carbon atoms if it replacestwo hydrogen atoms on the same carbon atom, or containing one to fivecarbon atoms if it replaces two hydrogen atoms on adjacent carbon atoms,or containing one to four carbon atoms if it replaces two hydrogen atomson carbon atoms which are separated by a further atom, or containing oneto three carbon atoms if it replaces two hydrogen atoms on carbon atomswhich are separated by two further atoms, whilst the above groups mayeach be substituted by one or two alkyl groups, or

C together with A and B denotes a pyridyl or 1-(4-pyridyl)-piperidinylgroup, each optionally substituted by one or two alkyl groups, or apiperidinyl group, in which the hydrogen atom in the 1-position togetherwith a hydrogen atom in the 2-position is replaced by a straight-chainedC₃₋₄ -alkylene group, or a piperidinyl group in which the hydrogen atomin the 1-position together with a hydrogen atom in the 3-position isreplaced by a straight-chained C₂₋₄ -alkylene group, or a piperidinylgroup in which the hydrogen atom in the 1-position together with ahydrogen atom in the 4-position is replaced by a straight chained C₁₋₃-alkylene group, whilst the methylene group of an ethylene chain boundto the 4-position may be replaced by a hydroxymethylene or carbonylgroup, and additionally the nitrogen atom of these above mentionedbicyclic groups, which may be substituted by one or two alkyl groups inthe carbon skeleton, may be complexed by borane or quaternised by abenzyl group optionally substituted by one to two methoxy groups in thephenyl nucleus, or

C denotes a C₁₋₆ -alkylene group and B denotes a bond,

(vi) D denotes a 1,3-arylene group,

an indanylene, naphthylene, 1,2,3,4-tetrahydronaphthylene orbenzosuberanylene group, wherein the saturated rings may each besubstituted by one or two alkyl groups and the aromatic rings may eachbe substituted by a fluorine, chlorine, bromine or iodine atom or by analkyl, trifluoromethyl, hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl,alkylsulphonyl or cyano group and wherein, additionally, one or twomethine groups may each be replaced by a nitrogen atom,

a C₃₋₇ -cycloalkylene group optionally substituted by one or two alkylgroups or

a cyclohexylene group in which two carbon atoms separated by three bondsmay additionally be linked by a straight-chained C₁₋₃ -alkylene group,whilst these bicyclic groups may each also be substituted by one to twoalkyl groups,

(vii) E denotes a straight chained C₁₋₆ -alkylene group or astraight-chained C₂₋₆ -alkenylene group, each is substituted by a C₁₋₈-alkyl group, by an aryl or heteroaryl group, by an HNR₆ orN-phenylalkyl-NR₆ group or by an N-alkyl NR₆ group having 1 to 8 carbonatoms in the alkyl moiety,

a C₅₋₇ -cycloalkylene group optionally substituted by one or two alkylgroups and wherein a >CH unit is replaced by a nitrogen atom,

a cycloalkylene group having 4 to 7 carbon atoms in the cycloalkylenemoiety which is substituted by a hydroxy, amino, aryl or heteroarylgroup, by a C₁₋₈ -alkoxy or C₁₋₈ -alkylamino group, by a dialkylaminogroup having a total of 2 to 10 carbon atoms, by an HNR₆ orN-phenylalkyl-NR₆ group or by an N-alkyl-NR₆ group having 1 to 8 carbonatoms in the alkyl moiety, or

an alkylene group linked to the group D via a group W, whilst thealkylene group may additionally be substituted by one or two C₁₋₈ -alkylgroups, by a hydroxy, amino, aryl or heteroaryl group, by a C₁₋₈ -alkoxyor C₁₋₈ -alkylamino group, by a dialkylamino group having a total of 2to 10 carbon atoms, by an HNR₆ or N-phenylalkyl-NR₆ group or by anN-alkyl-NR₆ group having 1 to 8 carbon atoms in the alkyl moiety,

(viii) F-denotes an alkoxy carbonyl group having a total of 3 to 9carbon atoms, an R₇ O--CO--, phosphono, O-alkyl-phosphono,O,O'-dialkylphosphono, tetrazol-5-yl or R₈ CO--O--CHR₉ --O--CO-- groupand

(ix) the third of the groups R_(a) to R_(d) denotes a perfluoroalkyl oraryl group;

those wherein:

X denotes a carbimino group optionally substituted at the nitrogen atomby an alkyl or cyano group, or X denotes a carbonyl, thiocarbonyl,sulphonyl, 1-nitro-ethen-2,2-diyl or 1,1-dicyano-ethen-2,2-diyl group;

Y denotes a straight-chained C₂₋₄ -alkylene group optionally substitutedby R_(c) or R_(d) or by R_(c) and R_(d), and which may additionally besubstituted by one or two alkyl groups, and wherein, additionally, oneor two methylene groups may each be replaced by a carbonyl group,

or Y denotes a straight-chained C₂₋₄ -alkenylene group optionallysubstituted by R_(c) or R_(d) or by R_(c) and R_(d), whereinadditionally any methylene group present may be replaced by a carbonylgroup,

or Y denotes a C₅₋₇ -1,2-cycloalkylene group optionally substituted byR_(c) or R_(d) or by R_(c) and R_(d),

or Y denotes a C₅₋₇ -1,2-cycloalkenylene group optionally substituted byR_(c) or R_(d) or by R_(c) and R_(d),

or Y denotes a 1,2-arylene group,

a 1,2-phenylene group in which one or two methine groups are eachreplaced by a nitrogen atom or wherein one or two --CH═CH-- groups areeach replaced by a --CO--NH-- group or wherein a methine group isreplaced by a nitrogen atom and a --CH═CH-- group by a --CO--NH-- group,whilst the above mentioned heterocyclic groups may additionally besubstituted by one or two alkyl groups, or

a --CO--NH--, --NH--CO--, --CH═N-- or --N═CH-- group optionallysubstituted by R_(c) or R_(d) ;

a first of the groups R_(a) to R_(d) denotes a group of the formula

    A--B--C--

(wherein A denotes a C₁₋₅ -aminoalkyl group, or an amino, amidino orguanidino group, in which, at one of the nitrogen atoms of the abovementioned groups one or two hydrogen atoms may each be replaced by analkyl group or a hydrogen atom may be replaced by an alkoxycarbonylgroup having a total of 2 to 5 carbon atoms, by a benzyloxycarbonylgroup or by an R₁ --CO--O--(R₂ CR₃)--O--CO-- group, wherein

R₁ denotes a C₁₋₈ -alkyl group, a C₅₋₇ -cycloalkyl group or a phenyl orphenylalkyl group,

R₂ denotes a hydrogen atom, an alkyl group, a C₅₋₇ -cycloalkyl group ora phenyl group, and

R₃ denotes a hydrogen atom or an alkyl group,

or A denotes a cyano or cyanoalkyl group or

if A is bound to a nitrogen atom of the groups B or C which is not partof a lactam group, A may also represent a hydrogen atom, an alkyl group,a benzyl group in which the phenyl moiety may be substituted by 1 to 2methoxy groups, a formyl, acetyl or trifluoroacetyl group, analkoxycarbonyl group having a total of 2 to 5 carbon atoms, abenzyloxycarbonyl group or an R₁ --CO--O--(R₂ CR₃)--O--CO-- group,wherein R₁ to R₃ are as hereinbefore defined;

B denotes a bond,

a C₁₋₆ -alkylene group,

an arylene group,

a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group inwhich one or two --CH═N-- groups may each be replaced by a --CO--NH--group and one of the nitrogen atoms, instead of being bound to ahydrogen atom, may also be bound to the group C, provided that thelatter does not have a heteroatom or carbonyl group adjoining the groupB, and wherein the above mentioned heterocyclic groups may additionallybe substituted by one or two alkyl groups,

or B denotes a C₃₋₇ -cycloalkylene group optionally substituted by oneor two alkyl groups,

a C₄₋₅ -cycloalkylene group optionally substituted by a group R_(c) andwhich may additionally be substituted by 1 to 4 alkyl groups andwherein, in the cycloalkylene moiety, a >CH unit is replaced by anitrogen atom which is linked to the group A, wherein,

with the proviso that a heteroatom of the group R_(c) is separated fromthe cyclic nitrogen atom of the cyclic imino group by at least twocarbon atoms, R_(c) represents an alkyl, hydroxy, alkoxy, phenylalkoxy,alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, cyano, carboxy,alkoxycarbonyl, phenylalkoxycarbonyl, alkylcarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, amino, alkylamino,dialkylamino or phenyl group,

or B denotes a C₆₋₈ -cycloalkylene group which is optionally substitutedby a group R_(c) and which may additionally be substituted by 1 to 4alkyl groups and wherein, in the cycloalkylene moiety, a >CH unit isreplaced by a nitrogen atom which is linked to the group A andadditionally another >CH unit in the 4-position may be replaced by anitrogen atom, whilst, moreover, in the above mentioned 6-8-memberedrings one or two methylene groups adjacent to a nitrogen atom may eachbe replaced by a carbonyl group, whilst R_(c) is as hereinbeforedefined,

or B denotes a C₅₋₇ -cycloalkenylene group optionally substituted by oneor two alkyl groups and which may additionally be substituted by one ortwo methyl groups and wherein, in the cycloalkenylene moiety, a >CH unitis replaced by a nitrogen atom which is linked to the group A, thenitrogen atom being separated from the double bond by means of at leastone optionally mono- or disubstituted methylene group,

or B denotes a C₅₋₇ cycloalkylene group wherein a >CH unit is replacedby a nitrogen atom linked to the group A and additionally two hydrogenatoms on the carbon skeleton are replaced by a straight-chained alkylenebridge, this bridge containing 2 to 6 carbon atoms if it replaces twohydrogen atoms on the same carbon atom, or containing 1 to 5 carbonatoms if it replaces two hydrogen atoms on adjacent carbon atoms, orcontaining 1 to 4 carbon atoms if it replaces two hydrogen atoms oncarbon atoms which are separated by a further atom, or containing 1 to 3carbon atoms if it replaces two hydrogen atoms on carbon atoms which areseparated by two further atoms, in which the above groups may each besubstituted by one or two alkyl groups,

or B denotes a C₁₋₆ -alkylene group linked to group C via a group W,wherein W denotes an oxygen or sulphur atom or a sulphinyl, sulphonyl,NR₄, NR₅ CO or CONR₅ group, wherein

R₄ denotes a hydrogen atom or an alkyl, alkylcarbonyl, alkylsulphonyl,arylcarbonyl, heteroarylcarbonyl, arylsulphonyl or heteroarylsulphonylgroup and

R₅ denotes a hydrogen atom or an alkyl group,

or B together with A denotes a pyridyl group optionally substituted byone or two alkyl groups or a piperidinyl group, in which the hydrogenatom in the 1-position together with a hydrogen atom in the 2-positionis replaced by a straight-chained C₃₋₄ -alkylene group, or B togetherwith A denotes a piperidinyl group, in which the hydrogen atom in the1-position together with a hydrogen atom in the 3-position is replace dby a straight-chained C₂₋₄ -alkylene group, or B together with A denotesa piperidinyl group in which the hydrogen atom in the 1-positiontogether with a hydrogen atom in the 4-position is replaced by astraight-chained C₁₋₃ -alkylene group, wherein the methylene group of anethylene chain bound to the 4-position may be replaced by ahydroxymethylene or carbonyl group and additionally the nitrogen atom ofthese above mentioned bicyclic groups, which may be substituted by oneor two alkyl groups in the carbon skeleton, may be complexed by boraneor quaternised by a benzyl group which is optionally substituted by 1 to2 methoxy groups in the phenyl nucleus; and

C denotes a C₁₋₆ -alkylene group wherein a methylene group may bereplaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl orNR₄ group, or wherein an ethylene group may be replaced by a CONR₅ orNR₅ CO group, wherein R₄ and R₅ are as hereinbefore defined,

or C denotes a C₂₋₆ -alkenylene group,

an alkylene carbonyl group, having a total of 2 to 7 carbon atoms, whichis linked to the group B via the carbonyl group,

an arylene group,

a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group,wherein one or two --CH═N-- groups may each be replaced by a --CO--NH--group and one of the nitrogen atoms, instead of being bound to ahydrogen atom, may also be bound to the group B, provided that B doesnot denote a bond and does not adjoin the group C with a heteroatom or acarbonyl group, wherein the above mentioned heterocyclic groups mayadditionally be substituted by one or two alkyl groups,

or C denotes a 3-7-membered cycloalkylene group optionally substitutedby one or two alkyl groups or

a cyclohexylene group in which two carbon atoms separated by three bondsare linked by a straight-chained C₁₋₃ -alkylene group, whilst thesebicyclic groups may additionally be substituted by one or two alkylgroups; or

C together with A and B denotes a pyridyl or 1-(4-pyridyl)-piperidinylgroup optionally substituted by one or two alkyl groups, or apiperidinyl group, in which the hydrogen atom in the 1-position togetherwith a hydrogen atom in the 2-position is replaced by a straight chainedC₃₋₄ -alkylene group, or C together with A and B denotes a piperidinylgroup in which the hydrogen atom in the 1-position together with ahydrogen atom in the 3-position is replaced by-a straight-chained C₂₋₄-alkylene group, or C together with A and B denotes a piperidinyl groupin which the hydrogen atom in the 1-position together with a hydrogenatom in the 4-position is replaced by a straight-chained C₁₋₃ -alkylenegroup, whilst the 4-position bound methylene-group of an ethylene chainmay be replaced by a hydroxymethylene or carbonyl group and additionallythe nitrogen atom of these above mentioned bicyclic groups which. may besubstituted by one or two alkyl groups in the carbon skeleton may becomplexed by borane or quaternised by a benzyl group which is optionallysubstituted by 1 to 2 methoxy groups in the phenyl nucleus; or

if B denotes a bond, C may also represent

(a) an indanylene, naphthylene, 1,2,3,4-tetrahydronaphthylene orbenzosuberanylene group, in which one of the rings is bound to the groupA and the other ring is bound to the cyclic group of general formula I,whilst the saturated rings may each be substituted by one or two alkylgroups and the aromatic rings may each be substituted by a fluorine,chlorine, bromine or iodine atom or by an alkyl, trifluoromethyl,hydroxy, alkoxy, aklylsulphenyl, alkylsulphinyl, alkylsulphonyl or cyanogroup and wherein, additionally, one or two methine groups may each bereplaced by a nitrogen atom,

(b) a C₄₋₅ -cycloalkylene group optionally substituted by the group Rtand which may additionally be substituted by 1 to 4 alkyl groups andwherein, in the cycloalkylene moiety, a >CH unit is replaced by anitrogen atom linked to the group A, wherein R_(c) is as hereinbeforedefined,

(c) a C₆₋₈ -cycloalkylene group optionally substituted by the groupR_(c) and which may additionally be substituted by 1 to 4 alkyl groupsand wherein, in the cycloalkylene moiety, a >CH unit is replaced by anitrogen atom linked to the group A and additionally another >CH-unit inthe 4-position may be replaced by a nitrogen atom, whilst furthermore,in the above mentioned 6-8-membered rings, one or two methylene groupsadjacent to a nitrogen atom may each be replaced by a carbonyl group,whilst R_(c) is as hereinbefore defined,

(d) a C₅₋₇ -cycloalkenylene group optionally substituted by one or twoalkyl groups and which may additionally be substituted by one or twomethyl groups and wherein, in the cycloalkenylene moiety, a >CH unit isreplaced by a nitrogen atom linked to the group A, whilst the nitrogenatom is separated from the double bond by at least one optionally mono-or di-substituted methylene group, or

(e) a C₅₋₇ -cycloalkylene group wherein a >CH unit is replaced by anitrogen atom linked to the group A and additionally two hydrogen atomson the carbon skeleton are replaced by a straight-chained alkylenebridge, this bridge containing 2 to 6 carbon atoms if it replaces twohydrogen atoms on the same carbon atom, or containing 1 to 5 carbonatoms if it replaces two hydrogen atoms on adjacent carbon atoms, orcontaining 1 to 4 carbon atoms if it replaces two hydrogen atoms oncarbon atoms separated by a further atom, or containing 1 to 3 carbonatoms if it replaces two hydrogen atoms on carbon atoms separated by twofurther atoms in which the above groups may each be substituted by oneor two alkyl groups);

a second of groups R_(a) to R_(d) denotes a group of the formula

    F--E--D--

(wherein D denotes a C₁₋₆ -alkylene group in which a methylene group maybe replaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl orNR₄ group, or wherein an ethylene group may be replaced by a CO--NR₅ orNR₅ --CO group wherein R₄ and R₅ are as hereinbefore defined,

a C₂₋₆ -alkenylene group,

an arylene group,

a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group inwhich one or two --CH═N-- groups may each be replaced by a --CO--NH--group and one of the nitrogen atoms, instead of being bound to ahydrogen atom, may also be bound to the group E provided that E does notrepresent a bond or does not adjoin the group D with a heteroatom or acarbonyl group, whilst the above mentioned heterocyclic groups mayadditionally be substituted by one or two alkyl groups,

or D denotes an indanylene, naphthylene, 1,2,3,4-tetrahydronaphthyleneor benzosuberanylene group, in which one of the rings is bound to thegroup E and the other ring is bound to the cyclic group of generalformula I, whilst the saturated rings may each be substituted by one ortwo alkyl groups and the aromatic rings may each be substituted by afluorine, chlorine, bromine or iodine atom or by an alkyl,trifluoromethyl, hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl,alkylsulphonyl or cyano group and wherein additionally one or twomethine groups may each be replaced by a nitrogen atom,

or D denotes a C₃₋₇ -cycloalkylene group optionally substituted by oneor two alkyl groups,

a C₄₋₇ -cycloalkylene group optionally substituted by one or two alkylgroups, wherein a >CH unit is replaced by a nitrogen atom, andfurthermore in the above mentioned 4-7-membered rings one, or for a ringsize of at least 5 one or two, methylene groups adjacent to a nitrogenatom may each be replaced by a carbonyl group,

a C₁₋₇ -cycloalkylene group optionally substituted by one or two alkylgroups, wherein two >CH units located in the 1,4-position relative toeach other are each replaced by a nitrogen atom, whilst moreover in theabove mentioned 6- or 7-membered rings one or two methylene groupsadjacent to a nitrogen atom may each be replaced by a carbonyl group,

a cyclohexylene group in which two carbon atoms separated by three bondsare linked by a straight-chained C₁₋₃ -alkylene groups, whilst thesebicyclic groups may also be substituted by 1 to 2 alkyl groups,

or, if E is a cyclic imino group, D may also represent analkylenecarbonyl group having a total of 2 to 6 carbon atoms, whereinthe carbonyl group in each case is bound to the nitrogen atom of thecyclic imino group of the group E,

or, if E does not represent a bond, D may represent a bond;

E denotes a bond, a C₁₋₆ -alkylene group or a C₂₋₆ -alkenylene groupeach of which may be substituted by one or two C₁₋₈ -alkyl groups, by ahydroxy, amino, aryl or heteroaryl group, by a C₁₋₈ -alkoxy or C₁₋₈-alkylamino group, by a dialkylamino group having a total of 2 to 10carbon atoms, by an HNR₆ or N-phenylalkyl-NR₆ group or by an N-alkyl-NR₆group having 1 to 8 carbon atoms in the alkyl moiety, wherein

R_(c) denotes an alkylcarbonyl or alkylsulphonyl group each having 1 to8 carbon atoms in the alkyl moiety, an alkyloxycarbonyl group having atotal of 2 to 5 carbon atoms, a cycloalkylcarbonyl orcycloalkyl-sulphonyl group each having 5 to 7 carbon atoms in thecycloalkyl moiety, an arylalkylcarbonyl, arylalkylsulphonyl,arylalkoxycarbonyl, arylcarbonyl, arylsulphonyl,heteroarylalkylcarbonyl, heteroarylalkylsulphonyl,heteroarylalkoxycarbonyl, heteroarylcarbonyl or heteroarylsulphonylgroup,

an arylene group,

a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group,wherein one or two CH═N groups may each be replaced by a CO--NH groupand one of the nitrogen atoms, instead of being bound to a hydrogenatom, may also be bound to the group Do provided that D does not denotea bond and D does not adjoin the group E with a heteroatom or a carbonylgroup, whilst the above mentioned heterocyclic groups may additionallybe substituted by one or two alkyl groups,

a C₅₋₇ -cycloalkylene group optionally substituted by one or two alkylgroups, wherein a >CH unit is replaced by a nitrogen atom which islinked to a carbon atom of the group D,

a cycloalkylene group having 4 to 7 carbon atoms in the cycloalkylenemoiety, optionally substituted by one or two C₁₋₈ -alkyl groups or by ahydroxy, amino, aryl or heteroaryl group, by an alkoxy or alkylaminogroup having 1 to 8 carbon atoms, by a dialkylamino group having a totalof 2 to 10 carbon atoms, by a n HNR₆ or N-phenylalkyl-NR₆ group or by anN-alkyl-NR₆ group having 1 to 8 carbon atoms in the alkyl moiety, whilstR₆ is as hereinbef ore defined,

or, if D does not denote a bond, E may denote an alkylene group linkedto the group D via a group W, wherein W is as hereinbefore defined andthe alkylene group may additionally be substituted by one or two C₁₋₈-alkyl groups, by a hydroxy,

amino, aryl or heteroaryl group, by an alkoxy or alkylamino group eachhaving 1 to 8 carbon atoms, by a dialkylamino group having a total of 2to 10 carbon atoms, by an HNR₆ or N-phenylalkyl-NR₆ group or by anN-alkyl-NR₆ group having 1 to 8 carbon atoms in the alkyl moiety, whilstthe heteroatom of the additional substituent is separated by at leasttwo carbon atoms from a heteroatom of group W and R₆ is as hereinbeforedefined, and with the proviso that D together with E does not representa (CH₂)_(n) --CONH--CH₂ CH₂ group, wherein

n denotes the number 1, 2, 3 or 4 and the ethylene moiety attached tothe nitrogen atom may optionally be substituted as mentionedhereinbefore; and

F denotes a carbonyl group which is substituted by a hydroxy group, by aC₁₋₈ -alkoxy group, by an arylalkoxy group or by an R₇ O-- group,wherein

R₇ denotes a C₄₋₈ -cycloalkyl group or a cycloalkylalkyl group having 3to 8 carbon atoms in the cycloalkyl moiety, wherein the cycloalkyl groupmay be substituted by an alkyl group, by an alkyl group and by 1 to 3methyl groups, or by an alkoxy or dialkylamino group and additionally amethylene group in a 4-8-membered cycloalkyl moiety may be replaced byan oxygen or sulphur atom or by a sulphinyl, sulphonyl or alkylaminogroup, or R₇ may denote a bicycloalkyl or bicycloalkylalkyl groupwherein the bicycloalkyl moiety contains 6 to 10 carbon atoms and mayadditionally be substituted by 1 to 3 methyl groups, or R₇ may denote aC₉₋₁₂ -benzocycloalkyl group or an aryl group,

or F denotes a phosphono, O-alkyl-phosphono, O,O'-dialkylphosphono,tetrazol-5-yl or R₈ CO--O--CHR₉ --O--CO-- group, wherein

R₈ denotes a C₁₋₈ -alkyl or C₁₋₈ -alkoxy group, a cycloalkyl orcycloalkoxy group each having 5 to 7 carbon atoms in the cycloalkylmoiety or an aryl, aryloxy, arylalkyl or arylalkoxy group and

R₉ denotes a hydrogen atom, a C₅₋₇ -cycloalkyl group or an alkyl or arylgroup,

and the shortest distance between the group F and the furthest removednitrogen atom of the groups A--B--C amounts to at least 11 bonds);

the third of the groups R_(a) to R_(d) denotes a hydrogen atom, analkyl, perfluoroalkyl, alkoxy, alkylsulphenyl, alkylsulphinyl,alkylsulphonyl, amino, alkylamino, dialkylamino, aryl, arylalkyl,heteroaryl or heteroarylalkyl group; and

the fourth of the groups R_(a) to R_(d) denotes a hydrogen atom or analkyl, aryl or arylalkyl group;

wherein, unless otherwise specified

the aryl moieties mentioned in the definition of the above groups may betaken to mean a phenyl group which is monosubstituted by R₁₀, mono-, di-or tri-substituted by R₁₁, or monosubstituted by R₁₀ and additionallymono- or di-substituted by R₁₁, wherein the substituents may beidentical or different and

R₁₀ denotes a cyano, carboxy, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylsulphenyl,alkylsulphinyl, alkylsulphonyl, alkylsulphonyloxy, perfluoroalkyl,trifluoromethoxy, nitro, amino, alkylamino, dialkylamino,alkylcarbonylamino, phenylalkylcarbonylamino, phenylcarbonylamino,alkylsulphonylamino, phenylalkylsulphonylamino, phenylsulphonylamino,N-alkyl-alkylcarbonylamino, N-alkyl-phenylalkylcarbonylamino,N-Alkyl-phenylcarbonylamino, N-Alkyl-alkylsulfonylamino,N-alkyl-phenylalkylsulphonylamino, N-alkyl-phenylsulphonylamino,aminosulphonyl, alkylamino-sulphonyl or dialkylaminosulphonyl group and

R₁₁ denotes an alkyl, hydroxy or alkoxy group or a fluorine, chlorine,bromine or iodine atom, whilst two groups R₁₁, if they are bound toadjacent carbon atoms, may also represent a C₃₋₆ -alkylene group, a1,3-butadiene-1,4-diylene group or a methylenedioxy group,

the arylene moieties mentioned in the definition of the above groups maybe taken to mean a phenylene group which may be monosubtituted by R₁₀,mono- or di-substituted by R₁₁, or monosubstituted by R₁₀ andadditionally monosubstituted by R₁₁, whilst the substituents may beidentical or different and are defined as hereinbefore,

the heteroaryl moieties mentioned in the definition of the above groupsmay be taken to mean a 5-membered heteroaromatic ring which contains anoxygen, sulphur or nitrogen atom, a nitrogen atom and an oxygen, sulphuror nitrogen atom, or two nitrogen atoms and an oxygen, sulphur ornitrogen atom, or a 6-membered heteroaromatic ring which contains 1, 2or 3 nitrogen atoms and wherein, additionally, one or two CH═N groupsmay each be replaced by a CO--NR₅ group, wherein R₅ is as hereinbeforedefined, and additionally the above mentioned heteraromatic rings may besubstituted by one or two alkyl groups or, on the carbon skeleton, by afluorine, chlorine, bromine or iodine atom or by a hydroxy or alkoxygroup,

and unless otherwise specified the above mentioned alkyl, alkylene oralkoxy moieties may each contain 1 to 4 carbon atoms and each carbonatom in the above mentioned alkylene and cycloalkylene moieties may belinked to not more than one heteroatom.

Preferred compounds of general formula I above are, with the exceptionof

1-4-(4-amidino-phenyl)-cyclohexyl!-3-(2-carboxy-ethyl)-imidazolidin-2-one,

1-4-(4-amidino-phenyl)-cyclohexyl!-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one,

1-4-(4-amidino-phenyl)-cyclohexyl!-3-(2-methoxycarbonyl-ethyl)-3H-imidazol-2-one,

1-4-(4-amidino-phenyl)-cyclohexyl!-3-(2-carboxy-ethyl)-3H-imidazol-2-one,

1-4-(4-cyano-phenyl)-cyclohexyl!-3-(2-ethoxycarbonyl-ethyl)-3H-imidazol-2-one,

1-(4-amidino-phenyl)-3-4-(2-carboxy-ethyl)-cyclohexyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-methoxycarbonyl-ethyl)-cyclohexyl!-imidazblidin-2-one,

1-(4-cyano-phenyl)-3-4-(2-methoxycarbonyl-ethyl)-cyclohexyl!-3H-idazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-phosphono-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3- 4-2-(O-methyl-phosphono)-ethyl!-phenyl!-imidazolidin-2-one,

1-(4-cyano-phenyl)-3- 4-(2-phosphono-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-cyano-phenyl)-3- 4-2-(O-methyl-phosphono)-ethyl!-phenyl!-imidazolidin-2-one,

1-(1-amidino-4-piperidinyl)-3-4-(2-carboxy-ethyl)-phenyl)-imidazolidin-2-one,

1-(1-amidino-4-piperidinyl)-3-4-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-aminomethyl-cyclohexyl)-3-4-(2-carboxy-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-aminomethyl-cyclohexyl)-3-4-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-carboxy-ethyl)-phenyl!-4-phenyl-3H-imidazol-2-one,

1-(4-amidino-phenyl)-3-4-(2-methoxycarbonyl-ethyl)-phenyl!-4-phenyl-3H-imidazol-2-one,

1-(4-amidino-phenyl)-3-4-(2-carboxy-ethyl)-phenyl!-4-phenyl-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-methoxycarbonyl-ethyl)-phenyl!-4-phenyl-imidazolidin-2-one,

4-(4-amidino-phenyl)-1-4-(2-carboxy-ethyl)-phenyl!-3-phenyl-3H-imidazol-2-one,

4-(4-amidino-phenyl)-1-4-(2-methoxycarbonyl-ethyl)-phenyl!-3-phenyl-3H-imidazol-2-one,

4-(4-cyano-phenyl)-1-4-(2-methoxycarbonyl-ethyl)-phenyl!-3-phenyl-3H-imidazol-2-one,

4-(4-amidino-phenyl)-1-4-(2-carboxy-ethyl)-phenyl!-3-phenyl-3H-imidazol-2-thione,

4-(4-amidino-phenyl)-1-4-(2-methoxycarbonyl-ethyl)-phenyl!-3-phenyl-3H-imidazol-2-thione,

4-(4-cyano-phenyl)-1-4-(2-methoxycarbonyl-ethyl)-phenyl!-3-phenyl-3H-imidazol-2-thione,

4-(4-amidino-phenyl)-1-4-(2-carboxy-ethyl)-phenyl!-5-methyl-3-phenyl-3H-imidazol-2-one,

4-(4-amidino-phenyl)-1-4-(2-methoxycarbonyl-ethyl)-phenyl!-5-methyl-3-phenyl-3H-imidazol-2-one,

4-(4-cyano-phenyl)-1-4-(2-methoxycarbonyl-ethyl)-phenyl!-5-methyl-3-phenyl-3H-imidazol-2-one,

4-(4-amidino-phenyl)-1-4-(2-carboxy-ethyl)-phenyl!-3-phenyl-imidazolidin-2-one,

4-(4-amidino-phenyl)-1-4-(2-methoxycarbonyl-ethyl)-phenyl!-3-phenyl-imidazolidin-2-one,

1-(4-amidino-phenyl)-4-4-(2-carboxy-ethyl)-phenyl!-3-phenyl-3H-imidazol-2-one,

1-(4-amidino-phenyl)-4-4-(2-methoxycarbonyl-ethyl)-phenyl!-3-phenyl-3H-imidazol-2-one,

1-(4-cyano-phenyl)-4-4-(2-methoxycarbonyl-ethyl)-phenyl!-3-phenyl-3H-imidazol-2-one,

1-(4-amidino-phenyl)-4-4-(2-carboxy-ethyl)-phenyl!-3-phenyl-imidazolidin-2-one,

1-(4-amidino-phenyl)-4-4-(2-methoxycarbonyl-ethyl)-phenyl!-3-phenyl-imidazolidin-2-one,

1-(4-amidino-phenyl)-4-4-(2-carboxy-ethyl)-phenyl!-3-phenyl-3H-imidazol-2-thione,

1-(4-amidino-phenyl)-4-4-(2-methoxycarbonyl-ethyl)-phenyl!-3-phenyl-3H-imidazol-2-thione,

1-(4-cyano-phenyl)-4-(4-(2-methoxycarbonyl-ethyl)-phenyl!-3-phenyl-3H-imidazol-2-thione,

1-(4-amidino-phenyl)-4-4-(2-carboxy-ethyl)-phenyl!-5-methyl-3-phenyl-3H-imidazol-2-one,

1-(4-amidino-phenyl)-4-(4-(2-methoxycarbonyl-ethyl)-phenyl!-5-methyl-3-phenyl-3H-imidazol-2-one,

1-(4-cyano-phenyl)-4-4-(2-methoxycarbonyl-ethyl)-phenyl!-5-methyl-3-phenyl-3H-imidazol-2-one,

4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-3-phenyl-3H-imidazol-2-one,

4-(4'-amidino-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3-phenyl-3H-imidazol-2-one,

4-(4'-cyano-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3-phenyl-3H-imidazol-2-one,

4-4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-3-phenyl-imidazolidin-2-one

4-(4'-amidino-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3-phenyl-imidazolidin-2-one,

4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-3-phenyl-3H-imidazol-2-thione,

4-(4'-amidino-4-biphenylyl)-1-(2-methoxycarbonylethyl)-3-phenyl-3H-imidazol-2-thione,

4-(4'-cyano-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3-phenyl-3H-imidazol-2-thione,

4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-5-methyl-3-phenyl-3H-imidazol-2-one,

4-(4'-amidino-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-5-methyl-3-phenyl-3H-imidazol-2-one,

4-(4'-cyano-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-5-methyl-3-phenyl-3H-imidazol-2-one,

1-(4-amidino-phenyl)-3-4-(2-butyloxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4'-amidino-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-3H-imidazol-2-one,

1-(4'-cyano-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-3H-imidazol-2-one,

1-(4'-amidino-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-imidazolidin-2,4-dione,

1-(4'-cyano-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-imidazolidin-2,4-dione

1-(4'-amidino-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-3,4,5,6-tetrahydro-1H-pyrimidin-2-one,

1-(4'-cyano-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-3,4,5,6-tetrahydro-1H-pyrimidin-2-one,

2-(4-amidino-phenyl)-4-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

4-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-2-(4-methoxy-carbonylamidino-phenyl)-5-methyl-4H-1,2,4-triazol-3-one,

1-(4-amidino-phenyl)-3-4-(2-ethoxycarbonyl-ethyl)-phenyl!-3H-imidazol-2-one,

1-(4-ethoxycarbonylamidino-phenyl)-3-4-(2-ethoxycarbonyl-ethyl)-phenyl!-3H-imidazol-2-one,

1-(4-ethoxycarbonylamidino-phenyl)-3-4-(2-ethoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-methoxycarbonylamidino-phenyl)-3-4-(2-methoxycarbonyl-ethyl)-cyclohexyl!-imidazolidin-2-one,

4-4-(2-isobutyloxycarbonyl-ethyl)-phenyl!-2-(4-methoxy-carbonylamidino-phenyl)-5-methyl-4H-1,2,4-triazol-3-one,

2-(4-amidino-phenyl)-4-4-(2-isobutyloxycarbonyl-ethyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

1-(1-amino-5-indanyl)-3- 4-(2-carboxy-ethyl)-phenyl!-imidazolidin-2-one,

1-(1-amino-5-indanyl)-3-4-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(1-amino-1,2,3,4-tetrahydro-6-naphthyl)-3-4-(2-carboxy-ethyl)-phenyl!-imidazolidin-2-one,

1-(1-amino-1,2,3,4-tetrahydro-6-naphthyl)-3-4-(2-methoxy-carbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-amino-cyclohexyl)-3-4-(3-carboxy-propyl)-phenyl!-imidazolidin-2-one,

1-(4-amino-cyclohexyl)-3-4-(3-methoxycarbonyl-propyl)-phenyl!-imidazolidin-2-one,

1-(4-amino-cyclohexyl)-3-4-(2-carboxy-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-amino-cyclohexyl)-3-4-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-aminomethyl-phenyl)-3-3-(2-carboxy-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-aminomethyl-phenyl)-3-3-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-amino-cyclohexyl)-3- 4-(2-carboxy-ethyl)-aminocarbonyl!-phenyl!-imidazolidin-2-one,

1-(4-amino-cyclohexyl)-3- 4-(2-methoxycarbonyl-ethyl)-aminocarbonyl!-phenyl!-imidazolidin-2-one,

1- 4-(2-carboxy-ethyl)-aminocarbonyl!-phenyl!-3-(4-piperidinyl)-imidazolidin-2-one,

1- 4-(2-methoxycarbonyl-ethyl)-aminocarbonyl!-phenyl!-3-(4-piperidinyl)-imidazolidin-2-one,

1- 4-(1-amino-cyclopropyl)-phenyl!-3-4-(2-carboxyethyl)-phenyl!-imidazolidin-2-one,

1- 4-(1-amino-cyclopropyl)-phenyl!-3-4-(2-methoxycarbonyl-ethyl)-phenyl)-imidazolidin-2-one,

1- 4-(1-amino-cyclopentyl)-phenyl!-3-4-(2-carboxyethyl)-phenyl!-imidazolidin-2-one,

1- 4-(1-amino-cyclopentyl)-phenyl!-3-4-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

2-(4-amidino-phenyl)-5-ethyl-4-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-4H-1,2,4-triazol-3-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonylethyl)-phenyl!-4-methyl-3H-imidazol-2-one,

4-(4-amidino-phenyl)-2-4-(2-isopropyloxycarbonylethyl)-phenyl!-4H-1,2,4-triazol-3-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonylethyl)-phenyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonylethyl)-phenyl!-3H-imidazol-2-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonylethyl)-phenyl!-imidazolidin-2,4-dione,

1- 4-(2-carboxy-ethyl)-aminocarbonyl!-phenyl!-3-(1-methyl-4-piperidinyl)-imidazolidin-2-one,

2-(4-amidino-phenyl)-4-4-(2-phosphono-ethyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

2-(4-amidino-phenyl)-4- 4-2-(O-methyl-phosphono)-ethyl!-phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

2-(4-amidino-phenyl)-4-4-(2-carboxy-ethyl)-phenyl!-5-phenyl-4H-1,2,4-triazol-3-one,

2-(4-amidino-phenyl)-4-4-(2-methoxycarbonyl-ethyl)-phenyl!-5-phenyl-4H-1,2,4-triazol-3-one,

3-(4-amidino-phenyl)-1-4-(2-carboxy-ethyl)-phenyl!-4-trifluoromethyl-3H-imidazol-2-one,

3-(4-amidino-phenyl)-1-4-(2-methoxycarbonyl-ethyl)-phenyl!-4-trifluoromethyl-3H-imidazol-2-one,

2-(4-amidino-phenyl)-4-4-(2-carboxy-ethyl)-phenyl!-5-trifluoromethyl-4H-1,2,4-triazol-3-one,

2-(4-amidino-phenyl)-4-4-(2-methoxycarbonyl-ethyl)-phenyl!-5-trifluoromethyl-4H-1,2,4-triazol-3-oneand

3-(4-cyano-phenyl)-1-(4-ethoxycarbonyl-butyl)-3H-imidazo-4,5-b!pyridin-2-one,

and with the proviso that at least one of conditions (i) to (ix) belowis satisfied

(i) X denotes a carbimino group substituted at the nitrogen atom by acyano group,

(ii) Y denotes a C₅₋₇ -1,2-cycloalkylene group optionally substituted byR_(c) or R_(d) or by R_(c) and R_(d).

(iii) A denotes a C₁₋₅ -aminoalkyl group or an amino, amidino orguanidino group, wherein at one of the nitrogen atoms in each of theabove mentioned groups a hydrogen atom is replaced by an R₁ --CO--O--(R₂CR₃)--O--CO-- group,

(iv) B denotes a C₃₋₇ -cycloalkylene group optionally substituted by oneor two alkyl groups,

a C₄₋₅ -cycloalkylene group optionally substituted by a group R_(c) andwhich may additionally be substituted by 1 to 4 alkyl groups and inwhich, in the cycloalkylene moiety, a >CH unit is replaced by a nitrogenatom,

a C₆₋₈ -cycloalkylene group optionally substituted by a group R_(c) andwhich may additionally be substituted by 1 to 4 alkyl groups and inwhich, in the cycloalkylene moiety, a >CH unit is replaced by a nitrogenatom and additionally another >CH unit in the 4-position may be replacedby a nitrogen atom, whilst, moreover, in the above mentioned 6- to8-membered rings one or two methylene groups adjacent to a nitrogen atommay each be replaced by a carbonyl group,

a C₅₋₇ -cycloalkenylene group optionally substituted by 1 or 2 alkylgroups and which may additionally be substituted by 1 or 2 methyl groupsand wherein, in the cycloalkenylene moiety, a >CH unit is replaced by anitrogen atom,

a piperidinylene group in which two hydrogen atoms on the carbonskeleton are replaced by a straight-chained alkylene bridge, this bridgecontaining 2 to 6 carbon atoms if it replaces two hydrogen atoms on thesame carbon atom, or containing 1 to 5 carbon atoms if it replaces twohydrogen atoms on adjacent carbon atoms, or containing 1 to 4 carbonatoms if it replaces two hydrogen atoms on carbon atoms separated by afurther atom, or containing 1 to 3 carbon atoms if it replaces twohydrogen atoms on carbon atoms separated by 2 further atoms, in whichthe above groups may each be substituted by one or two alkyl groups,

an alkylene group linked to the group C via a group W,

or B together with A denotes a pyridyl group optionally substituted byone or two alkyl groups, or a piperidinyl group in which the hydrogenatom in the 1-position together with a hydrogen atom in the 2-positionis replaced by a straight-chained C₃₋₄ -alkylene group, or a piperidinylgroup in which the hydrogen atoms in the 1-position together with ahydrogen atom in the 3-position is replaced by a straight-chained C₂₋₄-alkylene group, or a piperidinyl group in which the hydrogen atom inthe 1-position together with a hydrogen atom in the 4-position isreplaced by a straight-chained C₁₋₃ -alkylene group, whilst a 4-positionbound methylene group of an ethylene chain may be replaced by ahydroxymethylene or carbonyl group and additionally the nitrogen atom ofthese above mentioned bicyclic groups, which may be substituted in thecarbon skeleton by 1 or 2 alkyl groups, may be completed by borane orquaternised by a benzyl group optionally substituted by one to twomethoxy groups in the phenyl nucleus,

(v) C denotes a C₁₋₆ -alkylene group in which a methylene group isreplaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl orNR₄ group or wherein an ethylene group is replaced by a CONR₅ or NR₅ COgroup,

a 5-7-membered cycloalkylene group optionally substituted by one or twoalkyl groups,

a cyclohexylene group in which two carbon atoms separated by three bondsare linked by a straight-chained C₁₋₃ -alkylene group, whilst thesebicyclic groups may also be substituted by one to two alkyl groups,

an indanylene, naphthylene, 1,2,3,4-tetrahydronaphthylene orbenzosuberanylene group, wherein the saturated rings may each besubstituted by one or two alkyl groups and the aromatic rings may eachbe substituted by a fluorine, chlorine, bromine or iodine atom, or by analkyl, trifluoromethyl, hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl,alkysulphonyl or cyano group,

a C₅₋₇ -cycloalkylene group optionally substituted by the group R_(c)and which may additionally be substituted by 1 to 4 alkyl groups andwherein, in the cycloalkylene moiety, a >CH unit is replaced by anitrogen atom,

a piperidinylene group in which two hydrogen atoms on the carbonskeleton are replaced by a straight-chained alkylene bridge, this bridgecontaining 2 to 6 carbon atoms if it replaces 2 hydrogen atoms on thesame carbon atom, or containing 1 to 5 carbon atoms if it replaces twohydrogen atoms on adjacent carbon atoms, or containing 1 to 4 carbonatoms if it replaces two hydrogen atoms on carbon atoms separated by afurther atom, or containing 1 to 3 carbon atoms if it replaces twohydrogen atoms on carbon atoms separated by two further atoms, in whichthe above groups may each be substituted by one or two alkyl groups,

or C together with A and B denotes a pyridyl or1-(4-pyridyl)-piperidinyl group optionally substituted by one or twoalkyl groups, or a piperidinyl group in which the hydrogen atom in the1-position together with a hydrogen atom in the 4-position is replacedby a straight-chained C₁₋₃ -alkylene group, whilst a 4-position boundmethylene group of an ethylene chain may be replaced by ahydroxymethylene or carbonyl group and additionally the nitrogen atom ofthese above mentioned bicyclic groups, which may be substituted in thecarbon skeleton by one or two alkyl groups, may be complexed by boraneor quaternised by a benzyl group optionally substituted by 1 to 2methoxy groups in the phenyl nucleus,

or C denotes a C₁₋₆ -alkylene group and B denotes a bond,

(vi) D denotes a 1,3-arylene group,

an indanylene, naphthylene, 1,2,3,4-tetrahydronaphthylene orbenzosuberanylene group, wherein the saturated rings may each besubstituted by one or two alkyl groups and the aromatic rings may eachbe substituted by a fluorine, chlorine, bromine or iodine atom or by analkyl, trifluoromethyl, hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl,alkylsulphonyl or cyano group,

a C₄₋₇ -cycloalkylene group optionally substituted by one or two alkylgroups or

a cyclohexylene group in which two carbon atoms separated by three bondsare linked by a straight-chained C₁₋₃ -alkylene group, whilst thesebicyclic groups may each also be substituted by one to two alkyl groups,

(vii) E denotes a straight-chained C₁₋₃ -alkylene group substituted by aC₁₋₆ -alkyl group, by an aryl group or by an HNR₆ - or N-alkyl-NR₆ -group,

a C₅₋₇ -cycloalkylene group optionally substituted by one or two alkylgroups and wherein a >CH unit is replaced by a nitrogen atom,

a cycloalkylene group having 4 to 7 carbon atoms in the cycloalkylenemoiety substituted by a hydroxy or amino group, by a C₁₋₆ -alkoxy groupor by an HNR₆ - or N-alkyl-NR₆ - group, or

E denotes an alkylene group linked to group D via a group W, wherein thealkylene group may additionally be substituted by one or two C₁₋₆ -alkylgroups, by a hydroxy, amino or aryl group, by a C₁₋₆ -alkoxy group or byan HNR₆ - or N-alkyl-NR₆ - group,

(viii) F denotes an alkoxycarbonyl group having a total of 3 to 9 carbonatoms, an R₇ O--CO--, phosphono, O-alkyl-phosphono,O,O'-dialkyl-phosphono or R₈ CO--O--CHR₉ --O--CO-- group and

(ix) the third of the groups R_(a) to R_(d) denotes a trifluoromethyl oraryl group;

those wherein:

X denotes a carbimino group optionally substituted at the nitrogen atomby an alkyl or cyano group, or X denotes a carbonyl, thiocarbonyl orsulphonyl group;

Y denotes a straight-chained C₂₋₃ -alkylene group optionally substitutedby R_(c) or R_(d) or by R_(c) and R_(d) and which may additionally besubstituted by one or two alkyl groups, and wherein, additionally, amethylene group may be replaced by a carbonyl group,

a straight-chained C₂₋₃ -alkenylene group optionally substituted byR_(c) or R_(d) or by R_(c) and R_(d), wherein additionally any methylenegroup present may be replaced by a carbonyl group,

a C₅₋₇ -1,2-cycloalkylene group optionally substituted by R_(c) or R_(d)or by R_(c) and R_(d),

a C₅₋₇ -1,2-cycloalkenylene group,

a 1,2-arylene group,

a 1,2-phenylene group in which one or two methine groups are eachreplaced by a nitrogen atom, whilst the above mentioned heterocyclicgroups may additionally be substituted by one or two alkyl groups, or

a CO--NH, NH--CO, CH═N or N═CH group optionally substituted by R_(c) orR_(d) ;

a first of the groups R_(a) to R_(d) denotes a group of the formula

    A--B--C--

(wherein A denotes a C₁₋₅ -aminoalkyl group, or an amino, amidino orguanidino group, whilst at one of the nitrogen atoms in each of theabove mentioned groups one or two hydrogen atoms may each be replaced byan alkyl group or one hydrogen atom may be replaced by an alkoxycarbonylgroup having a total of 2 to 5 carbon atoms, by a benzyloxycarbonylgroup or by an R₁ --CO--O--(R₂ CR₃)--O--CO-- group, wherein

R₁ denotes a C₁₋₈ -alkyl group, a C₅₋₇ -cycloalkyl group or a phenyl orphenylalkyl group,

R₂ denotes a hydrogen atom or an alkyl group and

R₃ denotes a hydrogen atom,

or A denotes a cyano or cyanoalkyl group,

or if A is bound to a nitrogen atom of groups B or C which is not partof a lactam group, A may also denote a hydrogen atom, an alkyl group abenzyl group wherein the phenyl moiety may be substituted by one to twomethoxy group, a formyl, acetyl or trifluoroacetyl group, analkoxycarbonyl group having a total of 2 to 5 carbon atoms, abenzyloxycarbonyl group, or an R₁ --CO--O--(R₂ CR₃)O--CO-- group,wherein R₁ to R₃ are as hereinbefore defined;

B denotes a bond,

an alkylene group,

an arylene group,

a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene groupoptionally substituted by one or two alkyl groups,

a C₃₋₇ -cycloalkylene group optionally substituted by one or two alkylgroups,

a C₄₋₅ -cycloalkylene group optionally substituted by a group R_(c) andwhich may additionally be substituted by 1 to 4 alkyl groups andwherein, in the cycloalkylene moiety, a >CH unit is replaced by anitrogen atom linked to the group A, wherein

with the proviso that any heteroatom of the group R_(c) is separatedfrom the cyclic nitrogen atom of the cyclic imino group by at least twocarbon atoms, R_(c) denotes an alkyl, hydroxy, alkoxy, cyano, carboxy,alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl ordialkylamino carbonyl group,

or B denotes a C₆₋₈ -cycloalkylene group optionally substituted by agroup R_(c) and which may additionally be substituted by 1 to 4 alkylgroups and wherein, in the cycloalkylene moiety, a >CH unit is replacedby a nitrogen atom linked to the group A and additionally another >CHunit located in the 4-position may be replaced by a nitrogen atom,whilst furthermore in the above mentioned 6- to 8-membered rings one ortwo methylene groups adjacent to a nitrogen atom may each be replaced bya carbonyl group, whilst R_(c) is as hereinbefore defined,

a C₅₋₇ -cycloalkenylene group optionally substituted by one or two alkylgroups and which may additionally be substituted by one or two methylgroups and wherein, in the cycloalkenylene moiety, a >CH unit isreplaced by a nitrogen atom linked to the group A, wherein the nitrogenatom is separated from the double bond by at least one optionally mono-or di-substituted amethylene group,

a piperidinylene group in which two hydrogen atoms on the carbonskeleton are replaced by a straight-chained alkylene bridge, this bridgecontaining 2 to 6 carbon atoms if it replaces two hydrogen atoms on thesame carbon atom, or containing 1 to 5 carbon atoms if it replaces twohydrogen atoms on adjacent carbon atoms, or containing 1 to 4 carbonatoms if it replaces two hydrogen atoms on carbon atoms separated by afurther atom, or containing 1 to 3 carbon atoms if it replaces twohydrogen atoms on carbon atoms separated by two further atoms, in whichthe above mentioned groups may each be substituted by one or two alkylgroups,

or B denotes an alkylene group linked to the group C via a group W,wherein W represents an oxygen or sulphur atom or a sulphinyl,sulphonyl, NR₄, NR₅ CO or CONR₅ group, wherein

R₄ denotes a hydrogen atom or an alkyl, alkylcarbonyl, alkylsulphonyl,arylcarbonyl or arylsulphonyl group and

R₅ denotes a hydrogen atom or an alkyl group,

or B together with A denotes a pyridyl group optionally substituted byone or two alkyl groups, or a piperidinyl group wherein the hydrogenatom in the 1-position together with a hydrogen atom in the 2-positionis replaced by a straight-chained C₃₋₄ -alkylene group, or a piperidinylgroup in which the hydrogen atom in the 1-position together with ahydrogen atom in the 3-position is replaced by a straight-chained C₂₋₄-alkylene group, or a piperidinyl group in which the hydrogen atom inthe 1-position together with a hydrogen atom in the 4-position isreplaced by a straight-chained C₁₋₃ -alkylene group, whilst a 4-positionbound methylene group of an ethylene chain may be replaced by ahydroxymethylene or carbonyl group and additionally the nitrogen atom ofthese above mentioned bicyclic groups, which may be substituted in thecarbon skeleton by one or two alkyl groups, may be completed by boraneor quaternised by a benzyl group optionally substituted by one to twomethoxy groups in the phenyl nucleus; and

C denotes a C₁₋₆ -alkylene group wherein a methylene group may bereplaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl orNR₄ group, or wherein an ethylene group may be replaced by a CONR₅ orNR₅ CO group, wherein R₄ and R₅ are as hereinbefore defined,

a C₂₋₆ -alkenylene group,

an alkylene carbonyl group having a total of 2 to 6 carbon atoms andlinked to the group B via the carbonyl group,

an arylene group,

a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group,wherein one or two CH═N groups may each be replaced by a CO--NH groupand one of the nitrogen atoms, instead of being bound to a hydrogenatom, may also be bound to the group B, provided that B does notrepresent a bond and B does not adjoin the group C with a heteroatom ora carbonyl group, whilst the above mentioned heterocyclic groups mayadditionally be substituted by one or two alkyl groups,

a 5- to 7-membered cycloalkylene group optionally substituted by one ortwo alkyl groups,

a cyclohexylene group in which two carbon atoms separated by three bondsare linked by a straight-chained C₁₋₃ -alkylene group, whilst thesebicyclic groups may also be substituted by 1 to 2 alkyl groups;

or C together with A and B denotes a pyridyl or 1,4-pyridyl-piperidinylgroup optionally substituted by one or two alkyl groups, or apiperidinyl group in which the hydrogen atom in the 1-position togetherwith a hydrogen atom in the 4-position is replaced by a straight-chainedC₁₋₃ -alkylene group, whilst a 4-position bound methylene group of anethylene chain may be replaced by a hydroxymethylene or carbonyl groupand additionally the nitrogen atom of these above mentioned bicyclicgroups, which may be substituted by one or two alkyl groups in thecarbon skeleton, may be completed by borane or quaternised by a benzylgroup optionally substituted by 1 to 2 methoxy groups in thephenylnucleus,

or if B denotes a bond, C may also represent

(a) an indanylene, naphthylene, 1,2,3,4-tetrahydronapthylene orbenzosuberanylene group wherein one of the rings is bound to the group Aand the other ring is bound to the cyclic group of general formula I,whilst the saturated rings may each be substituted by one or two alkylgroups and the aromatic rings may each be substituted by a fluorine,chlorine, bromine or iodine atom, or by an alkyl, trifluoromethyl,hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl or cyanogroup,

(b) a C₅₋₄ -cycloalkylene group optionally substituted by a group R_(c)and which may additionally be substituted by 1 to 4 alkyl groups andwherein, in the cycloalkylene moiety, a >CH unit is replaced by anitrogen atom linked to the group A, whilst R_(c) is as defined ashereinbefore, or

(c) a piperidinylene group in which two hydrogen atoms on the carbonskeleton are replaced by a straight-chained alkylene bridge, this bridgecontaining 2 to 6 carbon atoms if it replaces two hydrogen atoms on thesame carbon atom, or containing 1 to 5 carbon atoms if it replaces twohydrogen atoms on adjacent carbon atoms, or containing 1 to 4 carbonatoms if it replaces two hydrogen atoms on carbon atoms separated by afurther atom, or containing 1 to 3 carbon atoms if it replaces twohydrogen atoms on carbon atoms separated by two further atoms, in whichthe above mentioned groups may each be substituted by one or two alkylgroups);

a second of the groups R_(a) to R_(d) denotes a group of formula

    F--E--D--

(wherein D denotes a C₁₋₆ -alkylene group wherein a methylene group maybe replaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl orNR₄ group, or wherein an ethylene group may be replaced by a CO--NR₅ orNR₅ --CO group, where R₄ and R₅ are as hereinbefore defined,

an arylene group,

a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene groupwherein one or two CH=N groups may each be replaced by a CO--NH groupand one of the nitrogen atoms, instead of being bound to a hydrogenatom, may also be bound to the group E, provided that E does not denotea bond and E does not adjoin the group D with a heteroatom or a carbonylgroup, whilst the above mentioned heterocyclic groups may additionallybe substituted by one or two alkyl groups,

an indanylene, naphthylene, 1,2,3,4-tetrahydronapthalene orbenzosuberanylene group, in which one of the rings is bound to the groupE and the other ring is bound to the cyclic group of general formula I,whilst the saturated rings may each be substituted by one or two alkylgroups and the aromatic rings may each be substituted by a fluorine,chlorine, bromine or iodine atom or by an alkyl, trifluoromethyl,hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl or cyanogroup,

a C₄₋₇ -cycloalkylene group optionally substituted by one or two alkylgroups,

a C₅₋₇ -cycloalkylene group optionally substituted by one or two alkylgroups and wherein a >CH unit is replaced by a nitrogen atom, whilstfurthermore in the above mentioned 5-7-membered rings a methylene groupadjacent to a nitrogen atom may be replaced by a carbonyl group,

a piperazinylene group optionally substituted by one or two alkyl groupsand wherein a methylene group adjacent to a nitrogen atom may bereplaced by a carbonyl group,

a cyclohexylene group in which two carbon atoms separated by three bondsare linked by a straight-chained C₁₋₃ -alkylene group, whilst thesebicyclic groups may also be substituted by 1 to 2 alkyl groups,

or, if E is a cyclic imino group, D may also represent analkylenecarbonyl group having a total of 2 to 6 carbon atoms, whereinthe carbonyl group is bound to the nitrogen atom of the cyclic iminogroup of group E,

or, if E is not a bond, D may represent a bond;

E denotes a bond,

a C₁₋₆ -alkylene group which may be substituted by one or two C₁₋₆-alkyl groups, by a hydroxy, amino or aryl group, by a C₁₋₆ -alkoxygroup or by an HNR₆ - or N-alkyl-NR₆ - group, wherein

R₆ denotes an alkylcarbonyl or alkylsulphonyl group each having 1 to 6carbon atoms in the alkyl moiety, an alkyloxycarbonyl group having atotal of 2 to 5 carbon atoms, a cycloalkylcarbonyl orcycloalkylsulphonyl group each having 5 to 7 carbon atoms in thecycloalkyl moiety, or an arylalkylcarbonyl, arylalkylsulphonyl,arylalkoxycarbonyl, arylcarbonyl or arylsulphonyl group,

or E denotes a C₂₋₆ -alkenylene group,

an arylene group,

a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene groupoptionally substituted by one or two alkyl groups,

a C₅₋₇ -cycloalkylene group optionally substituted by one or two alkylgroups and wherein a >CH unit is replaced by a nitrogen atom linked to acarbon atom of group D,

a C₄₋₇ -cycloalkylene group optionally substituted by one or two C₁₋₆-alkyl groups, by a hydroxy, amino or aryl group, by a C₁₋₆ -alkoxygroup or by an HNR₆ - or N-alkyl-NR₆ - group, wherein R₆ is ashereinbefore defined,

or, if D does not represent a bond, E may denote an alkylene grouplinked to the group D via a group W, wherein W is as hereinbeforedefined and the alkylene group may additionally be substituted by one ortwo C₁₋₆ -alkyl groups, by a hydroxy, amino or aryl group, by a C₁₋₆-alkoxy group, or by an HNR₆ - or N-alkyl-NR₆ - group, in which theheteroatom of the additional substituent is separated from a heteroatomof group W by at least two carbon atoms and R₆ is as hereinbeforedefined, and with the proviso that D together with E does not representa --(CH₂)_(n) --CONH--CH₂ CH₂ -- group, wherein

n represents the number 1, 2, 3 or 4 and the ethylene moiety attached tothe nitrogen atom may optionally be substituted as hereinbeforedescribed, and

F denotes a carbonyl group substituted by a hydroxy group, by a C₁₋₈-alkoxy group, by an arylalkoxy group or by an R₇ O-- group, wherein

R₇ denotes a C₅₋₇ -cycloalkyl group or a cycloalkylalkyl group having 5to 7 carbon atoms in the cycloalkyl moiety, wherein the cycloalkyl groupmay be substituted by an alkyl group, by an alkyl group and by 1 to 3methyl groups, or by an alkoxy group, and additionally a methylene groupin a 5- to 7-membered cycloalkyl moiety may be replaced by an oxygenatom or by an alkylamino group, or R₇ denotes a C₉₋₁₂ benzocycloalkylgroup or an aryl group,

or F denotes a phosphono, O-alkyl-phosphono, O,O'-dialkyl-phosphono,tetrazol-5-yl or R₈ CO--O--CHR--O--CO-- group, wherein

R₈ denotes a C₁₋₈ -alkyl or C₁₋₈ -alkoxy group, a cycloalkyl orcycloalkyloxy group each having 5 to 7 carbon atoms in the cycloalkylmoiety, or an arylalkyl or arylalkoxy group and

R₉ denotes a hydrogen atom or an alkyl group, and the shortest distancebetween group F and the furthest removed nitrogen atom of the groupA--B--C-- amounts to at least 11 bonds;

a third of the groups R_(a) to R_(d) denotes a hydrogen atom or analkyl, trifluoromethyl, aryl or arylalkyl group); and

the fourth of the groups R_(a) to R_(d) denotes a hydrogen atom or analkyl or aryl group,

whereby unless otherwise specified

the aryl moieties mentioned in the definition of the above groups may betaken to mean a phenyl group which may be monosubstituted by R₁₀, mono-,di- or tri-substituted by R₁₁ or monosubstituted by R₁₀ and additionallymono- or di-substituted by R₁₁, whilst the substituents may be identicalor different, and

R₁₀ denotes a cyano, carboxy, aminocarbonyl, alkylamino-carbonyl,dialkylaminocarbonyl, alkoxycarbonyl, alkyl-carbonyl, alkylsulphenyl,alkylsulphinyl, alkylsulphonyl, alkylsulphonyloxy, trifluoromethyl,trifluoromethoxy, nitro, amino, alkylamino, dialkylamino,alkylcarbonylamino, phenylalkylcarbonylamino, phenylcarbonylamino,alkylsulphonylamino, phenylalkylsulphonylamino, phenylsulphonylamino,N-alkyl-alkylcarbonylamino, N-alkyl-phenylalkylcarbonylamino,N-alkyl-phenylcarbonylamino, N-alkyl-alkylsulphonylamino,N-alkyl-phenylalkylsulphonylamino, N-alkyl-phenylsulfonylamino,aminosulphonyl, alkyl-aminosulphonyl or dialkylaminosulphonyl group and

R₁₁ denotes an alkyl, hydroxy or alkoxy group or a fluorine, chlorine,bromine or iodine atom, whilst two groups R₁₁, if they are bound toadjacent carbon atoms, may also represent a C₃₋₆ -alkylene group, a1,3-butadiene-1,4-diylene group or a methylenedioxy group,

the arylene groups mentioned in the definition of the above groups maybe taken to mean a phenylene group which may be monosubstituted by R₁₀,mono- or di-substituted by R₁₁, or monosubstituted by R₁₀ andadditionally monosubstituted by R₁₁, whilst the substituents may beidentical or different and are defined as hereinbefore,

and unless otherwise specified the above mentioned alkyl, alkylene oralkoxy moieties may each contain 1 to 4 carbon atoms, and each carbonatom in the above mentioned alkylene and cycloalkylene moieties may belinked to not more than one heteroatom,

the tautomers, stereoisomers and salts thereof.

Particularly preferred compounds of general formula I above are, withthe exception of

1-(4-amidino-phenyl)-3-4-(2-carboxy-ethyl)-cyclohexyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-methoxycarbonyl-ethyl)-cyclohexyl!-imidazolidin-2-one,

1-(4-cyano-phenyl)-3-4-(2-methoxycarbonyl-ethyl)-cyclohexyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-phosphono-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-(4-2-(O-methyl-phosphono)-ethyl!-phenyl!-imidazolidin-2-one,

1-(4-cyano-phenyl)-3- 4-(2-phosphono-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-cyano-phenyl)-3- 4-2-(O-methyl-phosphono)-ethyl!-phenyl!-imidazolidin-2-one,

1-(4-aminomethyl-cyclohexyl)-3-4-(2-carboxy-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-aminomethyl-cyclohexyl)-3-4-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-(4-(2-carboxy-ethyl)-phenyl!-4-phenyl-3H-imidazol-2-one,

1-(4-amidino-phenyl)-3-4-(2-methoxycarbonyl-ethyl)-phenyl!-4-phenyl-3H-imidazol-2-one,

1-(4-amidino-phenyl)-3-4-(2-carboxy-ethyl)-phenyl!-4-phenyl-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-methoxycarbonyl-ethyl)-phenyl!-4-phenyl-imidazolidin-2-one,

4-(4-amidino-phenyl)-1-4-(2-carboxy-ethyl)-phenyl!-3-phenyl-3H-imidazol-2-one,

4-(4-amidino-phenyl)-1-4-(2-methoxycarbonyl-ethyl)-phenyl!-3-phenyl-3H-imidazol-2-one,

4-(4-cyano-phenyl)-1-4-(2-methoxycarbonyl-ethyl)-phenyl!-3-phenyl-3H-imidazol-2-one,

4-(4-amidino-phenyl)-1-4-(2-carboxy-ethyl)-phenyl!-5-methyl-3-phenyl-3H-imidazol-2-one,

4-(4-amidino-phenyl)-1-4-(2-methoxycarbonyl-ethyl)-phenyl!-5-methyl-3-phenyl-3H-imidazol-2-one,

4-(4-cyano-phenyl)-1-4-(2-methoxycarbonyl-ethyl)-phenyl!-5-methyl-3-phenyl-3H-imidazol-2-one,

4-(4-amidino-phenyl)-1-4-(2-carboxy-ethyl)-phenyl!-3-phenyl-imidazolidin-2-one,

4-(4-amidino-phenyl)-1-4-(2-methoxycarbonyl-ethyl)-phenyl!-3-phenyl-imidazolidin-2-one,

1-(4-amidino-phenyl)-4-4-(2-carboxy-ethyl)-phenyl!-3-phenyl-3H-imidazol-2-one,

1-(4-amidino-phenyl)-4-4-(2-methoxycarbonyl-ethyl)-phenyl!-3-phenyl-3H-imidazol-2-one,

1-(4-cyano-phenyl)-4-4-(2-methoxycarbonyl-ethyl)-phenyl!-3-phenyl-3H-imidazol -2-one,

1-(4-amidino-phenyl)-4-4-(2-carboxy-ethyl)-phenyl!-3-phenyl-imidazolidin-2-one,

1-(4-amidino-phenyl)-4-4-(2-methoxycarbonyl-ethyl)-phenyl!-3-phenyl-imidazolidin-2-one,

1-(4-amidino-phenyl)-4-4-(2-carboxy-ethyl)-phenyl!-5-methyl-3-phenyl-3H-imidazol-2-one,

1-(4-amidino-phenyl)-4-4-(2-methoxycarbonyl-ethyl)-phenyl!-5-methyl-3-phenyl-3H-imidazol-2-one,

1-(4-cyano-phenyl)-4-4-(2-methoxycarbonyl-ethyl)-phenyl!-5-methyl-3-phenyl-3H-imidazol-2-one,

1-(4-amidino-phenyl)-3-4-(2-butyloxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

2-(4-amidino-phenyl)-4-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

4-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-2-(4-methoxy-carbonylamidino-phenyl)-5-methyl-4H-1,2,4-triazol-3-one,

1-(4-amidino-phenyl)-3-4-(2-ethoxycarbonyl-ethyl)-phenyl!-3H-imidazol-2-one,

1-(4-ethoxycarbonylamidino-phenyl)-3-4-(2-ethoxycarbonyl-ethyl)-phenyl!-3H-imidazol-2-one,

1-(4-ethoxycarbonylamidino-phenyl)-3-4-(2-ethoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-methoxycarbonylamidino-phenyl)-3-4-(2-methoxycarbonyl-ethyl)-cyclohexyl!-imidazolidin-2-one,

4-4-(2-isobutyloxycarbonyl-ethyl)-phenyl!-2-(4-methoxy-carbonylamidino-phenyl)-5-methyl-4H-1,2,4-triazol-3-one,

2-(4-amidino-phenyl)-4-4-(2-isobutyloxycarbonyl-ethyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

1-(1-amino-5-indanyl)-3- 4-(2-carboxy-ethyl)-phenyl!-imidazolidin-2-one,

1-(1-amino-5-indanyl)-3-4-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(1-amino-1,2,3,4-tetrahydro-6-naphthyl)-3-4-(2-carboxy-ethyl)-phenyl)-imidazolidin-2-one,

1-(1-amino-1,2,3,4-tetrahydro-6-naphthyl)-3-4-(2-methoxy-carbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-amino-cyclohexyl)-3-4-(3-carboxy-propyl)-phenyl!-imidazolidin-2-one,

1-(4-amino-cyclohexyl)-3-4-(3-methoxycarbonyl-propyl)-phenyl!-imidazolidin-2-one,

1-(4-amino-cyclohexyl)-3-4-(2-carboxy-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-amino-cyclohexyl)-3-4-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-aminomethyl-phenyl)-3-3-(2-carboxy-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-aminomethyl-phenyl)-3-3-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1- 4-(1-amino-cyclopropyl)-phenyl!-3-4-(2-carboxyethyl)-phenyl!-imidazolidin-2-one,

1- 4-(1-amino-cyclopropyl)-phenyl!-3-4-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1- 4-(1-amino-cyclopentyl)-phenyl!-3-4-(2-carboxyethyl)-phenyl!-imidazolidin-2-one,

1- 4-(1-amino-cyclopentyl)-phenyl!-3- 4-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

2-(4-amidino-phenyl)-5-ethyl-4-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-4H-1,2,4-triazol-3-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonylethyl)-phenyl!-4-methyl-3H-imidazol-2-one,

4-(4-amidino-phenyl)-2-4-(2-isopropyloxycarbonylethyl)-phenyl!-4H-1,2,4-triazol-3-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonylethyl)-phenyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-3H-imidazol-2-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonylethyl)-phenyl!-imidazolidin-2,4-dione,

2-(4-amidino-phenyl)-4-4-(2-phosphono-ethyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

2-(4-amidino-phenyl)-4- 4-2-(O-methyl-phosphono)-ethyl!-phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

2-(4-amidino-phenyl)-4-4-(2-carboxy-ethyl)-phenyl!-5-phenyl-4H-1,2,4-triazol-3-one,

2-(4-amidino-phenyl)-4-4-(2-methoxycarbonyl-ethyl)-phenyl!-5-phenyl-4H-1,2,4-triazol-3-one,

3-(4-amidino-phenyl)-1-4-(2-carboxy-ethyl)-phenyl!-4-trifluoromethyl-3H-imidazol-2-one,

3-(4-amidino-phenyl)-1-4-(2-methoxycarbonyl-ethyl)-phenyl!-4-trifluoromethyl-3H-imidazol-2-one,

2-(4-amidino-phenyl)-4-4-(2-carboxy-ethyl)-phenyl!-5-trifluoromethyl-4H-1,2,4-triazol-3-one,

2-(4-amidino-phenyl)-4-(4-(2-methoxycarbonyl-ethyl)-phenyl!-5-trifluoromethyl-4H-1,2,4-triazol-3-oneand

3-(4-cyano-phenyl)-1-(4-ethoxycarbonyl-butyl)-3H-imidazo-4,5-b!pyridin-2-one

and with the proviso that at least one of conditions (i) to (ix) belowis satisfied

(i) X denotes a carbimino group substituted by-a cyano group at thenitrogen atom,

(ii) Y denotes a 1,2-cyclopentylene or 1,2-cyclohexylene groupoptionally substituted by one or two alkyl groups,

(iii) A denotes an amidino group substituted by an R₁ --CO--O--(R₂CR₃)--O--CO-- group,

(iv) B denotes a pyrrolidinylene group optionally substituted by one ortwo alkyl groups,

a piperidinylene group optionally substituted by 1 to 4 alkyl groups andwhich may additionally be substituted in the 4-position by a cyano,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylor alkoxy group,

a piperidinylene group in which two hydrogen atoms on the carbonskeleton are replaced by a straight-chained alkylene group, this bridgecontaining 2 to 5 carbon atoms if it replaces two hydrogen atoms on thesame carbon atom, or containing 1 to 4 carbon atoms if it replaces twohydrogen atoms on adjacent carbon atoms, or containing 2 to 3 carbonatoms if it replaces two hydrogen atoms on carbon atoms separated by afurther atom, or containing 1 or 2 carbon atoms if it replaces twohydrogen atoms on carbon atoms separated by two further atoms,

a 1,2,3,6-tetrahydro-pyridinylene group optionally substituted by one ortwo alkyl groups,

an azacycloheptylene group optionally substituted by one or two alkylgroups,

a piperazinylene group optionally substituted by one or two alkylgroups,

a 2-oxo-piperazinylene group optionally substituted by one or two alkylgroups,

an alkyleneoxy group,

a C₃₋₆ -cycloalkylene group optionally substituted by one or two alkylgroups or

B together with A denotes a pyridyl group optionally substituted by oneor two alkyl groups, or a piperidinyl group in which the hydrogen atomin the 1-position together with a hydrogen atom in the 4-position isreplaced by a methylene, ethylene or 1,3-propylene group, whilst a4-position bound methylene group of an ethylene chain may be replaced bya carbonyl or hydroxymethylene group, and additionally the nitrogen atomof the above mentioned bicyclic groups, which may additionally besubstituted by one or two alkyl groups in the carbon skeleton, may becomplexed by borane or quaternised by a benzyl group,

(v) C denotes an alkyleneoxy group,

a cyclohexylene group in which two carbons separated by three bonds canadditionally be linked by a methylene or ethylene group,

a piperidinylene group optionally substituted by one or two alkyl groupsor

an indanylene, napthylene or 1,2,3,4-tetrahydronaphthylene group or

C together with A and B denotes a pyridyl or 1-(4-pyridyl)-piperidinylgroup optionally substituted by one or two alkyl groups, or apiperidinyl group in which the hydrogen atom in the 1-position togetherwith a hydrogen atom in the 4-position is replaced by a methylene orethylene group and additionally the nitrogen atom of these abovementioned bicyclic groups, which may additionally be substituted by oneor two alkyl groups in the carbon skeleton, may be complexed by boraneor quaternised by a benzyl group, or

C denotes a C₁₋₆ -alkylene group and B is a bond,

(vi) D denotes a 1,3-arylene group,

a C₅₋₇ -cycloalkylene group optionally substituted by one or two alkylgroups,

a cyclohexylene group in which two carbon atoms separated by three bondsare additionally linked by a methylene or ethylene group,

or D denotes an indanylene, naphthylene or 1,2,3,4-tetrahydronaphthylenegroup,

(vii) E denotes a straight-chained alkylene group which is substitutedby a C₁₋₆ -alkyl group, by an aryl group or by an HNR₆ - group, analkyleneoxy group linked to the group D via the oxygen

atom, and which is substituted by a C₁₋₆ -alkyl group, by an aryl,hydroxy or amino group, by a C₁₋₆ -alkoxy group or by an HNR₆ - group,

or E denotes a piperidinylene group optionally substituted by one or twoalkyl groups,

(viii) F denotes an alkoxycarbonyl group having a total of 3 to 7 carbonatoms, an R₇ O--CO--, phosphono, O-alkyl-phosphono,O,O'-dialkyl-phosphono or R₈ CO--O--CHR₉ --O--CO-- group and

(ix) the third of the groups R_(a) to R_(d) denotes a trifluoromethyl oraryl group,

those wherein:

X denotes a carbimino group substituted by a cyano group at the nitrogenatom, or X denotes a carbonyl or sulphonyl group,

Y denotes a CH₂ CH₂, CH₂ CH₂ CH₂, CH═CH, CH₂ CO or COCH₂ groupoptionally substituted by R_(c) or by R_(c) and R_(d),

or Y denotes an N═CH or CH═N group optionally substituted by R_(c),

a 1,2-arylene group,

a 1,2-phenylene group in which one or two methine groups are eachreplaced by a nitrogen atom, whilst the above mentioned heterocyclicgroups may additionally be substituted by one or two alkyl groups,

or Y denotes a 1,2-cyclopentylene or 1,2-cyclohexylene group optionallysubstituted by one or two alkyl groups;

a first of the groups R_(a) to E_(d) denotes a group of the formula

    A--B--C--

(wherein A denotes an amidino group optionally substituted by analkoxycarbonyl group having a total of two or three carbon atoms or by abenzyloxycarbonyl or R₁ --CO--O--(R₂ CR₃)--O--CO-- group, wherein

R₁ denotes an alkyl group,

R₂ denotes a hydrogen atom or a methyl group and

R₃ denotes a hydrogen atom,

or A denotes a cyano, cyanomethyl, cyanoethyl, amino, aminomethyl,aminoethyl or aminopropyl group or, if A is bound to a nitrogen atom ofthe groups B or C, A may denote a hydrogen atom, a methyl, ethyl,benzyl, tert.butyloxycarbonyl, benzyloxycarbonyl, trifluoroacetyl or R₁--CO--O--(R₂ CR₃)--O--CO-- group, wherein R₁ to R₃ are as hereinbeforedefined,

B denotes a bond,

a pyrrolidinylene group optionally substituted by one or two alkylgroups,

a piperidinylene group optionally substituted by 1 to 4 alkyl groups,which may additionally be substituted in the 4-position by a cyano,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylor alkoxy group,

a piperidinylene group in which two hydrogen atoms on the carbonskeleton are replaced by a straight-chained alkylene group, this bridgecontaining 2 to 5 carbon atoms if it replaces two hydrogen atoms on thesame carbon atom, or containing 1 to 4 carbon atoms if it replaces twohydrogen atoms on adjacent carbon atoms, or containing 2 to 3 carbonatoms if it replaces two hydrogen atoms on carbon atoms separated by afurther atom, or containing one or two carbon atoms if it replaces twohydrogen atoms on carbon atoms separated by two further atoms,

a 1,2,3,6-tetrahydropyridinylene group optionally substituted by one ortwo alkyl groups,

an azacycloheptylene group optionally substituted by one or two alkylgroups,

a piperazinylene group optionally substituted by one or two alkylgroups, wherein a nitrogen atom of the cyclic imino groups mentionedabove in the definition of group B is linked to group A,

a 2-oxo-piperazinylene group optionally substituted by one or two alkylgroups, wherein the nitrogen atom in the 4-position is linked to thegroup A,

an alkylene group,

an alkyleneoxy group, wherein the oxygen atom is linked to the group Cand the nitrogen atoms of group A are separated from the oxygen atom byat least two carbon atoms,

a C₃₋₆ -cycloalkylene group optionally substituted by one or two alkylgroups

or B together with A denotes a pyridyl group optionally substituted byone or two alkyl groups, or a piperidinyl group in which the hydrogenatom in the 1-position together with a hydrogen atom in the 4-positionis replaced by a methylene, ethylene or 1,3-propylene group, whilst a4-position bound methylene group of an ethylene chain may be replaced bya carbonyl or hydroxymethylene group and additionally the nitrogen atomof the above mentioned bicyclic groups, which may additionally besubstituted by one or two alkyl groups in the carbon skeleton, may becomplexed by borane or quaternised by a benzyl group, and

C denotes a C₁₋₆ -alkylene group,

an alkyleneoxy group in which the oxygen atom is bound to a carbon atomof group B or to one of the bicyclic groups formed by B together with Aand between the oxygen atom of the alkyleneoxy group and the nitrogenatom of the cyclic group of general formula I there are at least twocarbon atoms,

a C₂₋₄ -alkenylene group, although this cannot be linked to a heteroatomof group A, of group B or of the cyclic group of general formula I via avinylene moiety,

or C denotes a cyclohexylene group in which two carbon atoms separatedby three bonds, are additionally linked by a methylene or ethylenegroup,

an arylene group or a pyridinylene, pyrimidinylene, pyrazinylene orpyridazinylene group optionally substituted by one or two alkyl groups,

if B denotes a piperazinylene group optionally substituted by one or twoalkyl groups, C may also denote an alkylenecarbonyl group, in which thecarbonyl group is attached to the optionally mono- or di-alkylsubstituted nitrogen atom of the piperazinylene B group,

or C together with A and B represents a pyridyl or1-(4-pyridyl)-piperidinyl group optionally substituted by one or twoalkyl groups, or a piperidinyl group in which the hydrogen atom in the1-position together with a hydrogen atom in the 4-position is replacedby a methylene or ethylene group, and additionally the nitrogen atom ofthese above mentioned bicyclic groups, which may additionally besubstituted by one or two alkyl groups in the carbon skeleton, may becomplexed by borane or quaternised by a benzyl group,

or if B denotes a bond, C may also represent a piperidinylene groupoptionally substituted by one or two alkyl groups, wherein the nitrogenatom is linked to the group A, or an indanylene, naphthylene or1,2,3,4-tetrahydro-naphthylene group, wherein one of the rings is boundto the group A and the other ring to the cyclic group of general formulaI);

a second of groups R_(a) to R_(d) denotes a group of formula

    F--E--D--

(wherein D denotes an alkylene group,

an arylene group,

a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene groupoptionally substituted by one or two alkyl groups,

a C₅₋₇ -cycloalkylene group optionally substituted by one or two alkylgroups,

a cyclohexylene group in which two carbon atoms separated by three bondsare additionally linked by a methylene or ethylene group,

an indanylene, naphthylene or 1,2,3,4-tetrahydronaphthylene group,wherein one of the rings is bound to the group E and the other ring tothe cyclic group of general formula I,

or, if E denotes a piperidinylene group optionally substituted by one ortwo alkyl groups, D may also denote an alkylenecarbonyl group in whichthe carbonyl group is attached to the optionally mono- or di-alkylsubstituted nitrogen atom of the piperidinylene E group;

E denotes a bond,

a C₂₋₄ -alkenylene group,

an alkylene group which may be substituted by a C₁₋₆ -alkyl group, by anaryl, hydroxy or amino group, by a C₁₋₆ -alkoxy group or by an HNR₆ -group, whilst

R₆ denotes an alkylcarbonyl or alkylsulphonyl group each having 1 to 6carbon atoms in the alkyl moiety, a cycloalkylcarbonyl orcycloalkylsulphonyl group each having 5 to 7 carbon atoms in thecycloalkyl moiety, or an arylcarbonyl, arylsulphonyl, arylalkylcarbonylor arylalkylsulphonyl group,

or E denotes an alkyleneoxy group linked to group D via the oxygen atomand which may be substituted by a C₁₋₆ -alkyl group, by an aryl, hydroxyor amino group, by a C₁₋₆ -alkoxy group or by an HNR₆ - group, in whichthe heteroatom of the additional substituent is separated from theoxygen atom of the alkyleneoxy group by at least two carbon atoms and R₆is as hereinbefore defined,

or E denotes an arylene group,

a cyclohexylene group optionally substituted by one or two alkyl groups

or, if D is an alkylenecarbonyl group, E may denote a piperidinylenegroup optionally substituted by one or two alkyl groups, wherein thenitrogen atom is linked to the carbonyl group of the alkylenecarbonylgroup of group D; and

F denotes a carbonyl group substituted by a hydroxy group, by a C₁₋₆-alkoxy group, by an arylalkoxy group or by an R₇ O-- group, wherein

R₇ denotes a C₅₋₇ -cycloalkyl group, a cycloalkylalkyl group having 5 to7 carbon atoms in the cycloalkyl moiety, a C₉₋₁₁ -benzocycloalkyl groupor an aryl group,

or F denotes a phosphono, O-alkyl-phosphono, O,O'-dialkyl-phosphono,tetrazol-5-yl or R₈ CO--O--CHR--O--CO-- group, wherein

R₈ denotes a cycloalkyl or cycloalkyloxy group each having 5 to 7 carbonatoms in the cycloalkyl moiety, a C₁₋₆ -alkyl or C₁₋₆ -alkoxy group and

R₉ denotes a hydrogen atom or an alkyl group,

and the shortest distance between group F and the furthest removednitrogen atom of the group A--B--C-- amounts to at least 11 bonds);

a third of the groups R_(a) to R_(d) denotes a hydrogen atom or analkyl, trifluoromethyl, aryl or arylalkyl group; and

the fourth of the groups R_(a) to R_(d) denotes a hydrogen atom or analkyl group,

whilst, unless otherwise specified,

the aryl moieties mentioned in the definition of the above mentionedgroups may be taken to mean a phenyl group which may be monosubstitutedby R₁₀, mono- or di-substituted by R₁₁, or monosubstituted by R₁₀ andadditionally monosubstituted by R₁₁, wherein the substituents may beidentical or different and

R₁₀ denotes a cyano, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylcarbonyl, alkylsulphenyl, alkylsulphinyl,alkylsulphonyl, alkylsulphonyloxy, trifluoromethyl, nitro, amino,alkylcarbonylamino, N-alkyl-alkylcarbonylamino, alkylsulfonylamino orN-alkyl-alkylsulphonylamino group and

R₁₁ denotes an alkyl, hydroxy or alkoxy group or a fluorine, chlorine orbromine atom, while two groups R₁₁ provided that they are bound toadjacent carbon atoms, may also denote a C₃₋₄ -alkylene group, a1,3-butadiene-1,4-diylene group or a methylenedioxy group,

the arylene moieties mentioned in the definition of the above mentionedgroups may be taken to mean a phenylene group which may bemonosubstituted by R₁₀, mono- or di-substituted by R₁₁, ormonosubstituted by R₁₀ and additionally monosubstituted by R₁₁, whereinthe substituents may be identical or different and are defined ashereinbefore,

and unless otherwise specified the above mentioned alkyl, alkylene oralkoxy moieties may each contain 1 to 4 carbon atoms and each carbonatom in the above mentioned alkylene and cycloalkylene moieties islinked to not more than one heteroatom,

particularly those compounds, with the exception of

1-(4-amidino-phenyl)-3-4-(2-carboxy-ethyl)-cyclohexyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-methoxycarbonyl-ethyl)-cyclohexyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-phosphono-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3- 4-2-(O-methyl-phosphono)-ethyl!-phenyl!-imidazolidin-2-one,

1-(4-aminomethyl-cyclohexyl)-3-4-(2-carboxy-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-aminomethyl-cyclohexyl)-3-4-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-butyloxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

2-(4-amidino-phenyl)-4-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

1-(4-amidino-phenyl)-3-4-(2-ethoxycarbonyl-ethyl)-phenyl!-3H-imidazol-2-one,

2-(4-amidino-phenyl)-4-4-(2-isobutyloxycarbonyl-ethyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

1-(4-amino-cyclohexyl)-3-4-(3-carboxy-propyl)-phenyl!-imidazolidin-2-one,

1-(4-amino-cyclohexyl)-3-4-(3-methoxycarbonyl-propyl)-phenyl!-imidazolidin-2-one,

1-(4-amino-cyclohexyl)-3-4-(2-carboxy-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-amino-cyclohexyl)-3-4-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-aminomethyl-phenyl)-3-3-(2-carboxy-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-aminomethyl-phenyl)-3-(3-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-4-methyl-3H-imidazol-2-one,

4-(4-amidino-phenyl)-2-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-4H-1,2,4-triazol-3-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-3H-imidazol-2-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-imidazolidin-2,4-dione,

2-(4-amidino-phenyl)-4-4-(2-phosphono-ethyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one and

2-(4-amidino-phenyl)-4- 4-2-(O-methyl-phosphono)-ethyl!-phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

and with the proviso that at least one of conditions (i) to (viii) belowmust be satisfied

(i) X denotes a carbimino group substituted at the nitrogen atom by acyano group,

(ii) Y denotes a 1,2-cyclohexylene group,

(iii) A denotes an amidino group substituted by an R₁ --CO--O--(R₂CR₃)--O--CO-- group,

(iv) B denotes a 1,3-pyrrolidinylene or 1,3-piperidinylene group,

a 1,4-piperidinylene group optionally substituted by one to four methylgroups and which may additionally be substituted in the 4-position by acyano or aminocarbonyl group,

a 1,4-azacycloheptylene group,

a 1,4-piperazinylene group,

a 2-oxo-1,4-piperazinylene group,

a --CH₂ CH₂ -- group, or

a 1,2-cyclopentylene group

or B together with A denotes a 4-piperidinyl group in which the hydrogenatom in the 1-position together with a hydrogen atom in the 4-positionis replaced by a methylene or ethylene group, wherein a 4-position boundmethylene group of an ethylene chain may be replaced by a carbonylgroup,

(v) C denotes an --O--CH₂ -- or --O--CH₂ CH₂ -- group,

a 1,4-cyclohexylene group in which a hydrogen atom in the 1-positiontogether with a hydrogen atom in the 4-position may be replaced by anethylene group,

a 1,4-piperidinylene group,

a 1,2,3,4-tetrahydro-2,6-naphthylene group

or C together with A and B denotes a 4-piperidinyl group in which thehydrogen atom in the 1-position together with a hydrogen atom in the4-position is replaced by a methylene or ethylene group, or

C denotes a C₁₋₄ -alkylene group and B is a bond,

(vi) D denotes a 1,3-phenylene group optionally substituted by afluorine or chlorine atom or by a methyl, trifluoromethyl or cyanogroup,

a 1,4-cyclohexylene group wherein a hydrogen atom in the 1-positiontogether with a hydrogen atom in the 4-position may be replaced by anethylene group,

or D denotes a 1,5-indanylene, 2,6-naphthylene or1,2,3,4-tetrahydro-2,6-naphthylene group,

(vii) E denotes a straight-chained C₁₋₄ -alkylene group which issubstituted by a C₁₋₄ -alkyl group, by a phenyl group or by a C₁₋₄-alkylsulphonylamino group, or

E denotes a 1,4-piperidinylene group,

(viii) F denotes an alkoxycarbonyl group having a total of 3 to 6 carbonatoms, or an R₇ --CO--, R₈ CO--O--CHR₉ --O--CO--, phosphono,O-methyl-phosphono or O-ethyl-phosphono group;

wherein:

X denotes a carbimino group substituted by a cyano group at the nitrogenatom, or X denotes a carbonyl or sulphonyl group;

Y denotes a CH₂ CH₂, CH₂ CH₂ CH₂, CH═CH, CH₂ CO or COCH₂ groupoptionally substituted by R_(c) or by R_(c) and R_(d),

an N═CH or CH═N group optionally substituted by R_(c),

or a 1,2-phenylene or 1,2-cyclohexylene group;

a first of groups R_(a) to R_(d) denotes a group of the formula

    A--B--C--

(wherein A denotes an amidino group optionally substituted by an R₁--CO--O--(R₂ CR₃)--O--CO-- group, wherein

R₁ denotes a methyl group,

R₂ denotes a hydrogen atom or a methyl group and

R₃ denotes a hydrogen atom,

or A denotes an amino or aminomethyl group or, if A is bound to anitrogen atom of groups B or C, it may also denote a hydrogen atom or amethyl group,

B denotes a bond,

a 1,3-pyrrolidinylene or 1,3-piperidinylene group,

a 1,4-piperidinylene group optionally substituted by one to four methylgroups and which may additionally be substituted in the 4-position by acyano or aminocarbonyl group,

a 1,4-azacycloheptylene group,

a 1,4-piperazinylene group, wherein a nitrogen atom of the groupmentioned above in the definition of group B is linked to group A,

a 2-oxo-1,4-piperazinylene group wherein the nitrogen atom in the4-position is linked to the group A,

a --CH₂ CH₂ O-- group, wherein the oxygen atom is linked to the group C,

a 1,2-cyclopentylene group,

or B together with A denotes a 4-piperidinyl group in which the hydrogenatom in the 1-position together with a hydrogen atom in the 4-positionis replaced by a methylene or ethylene group, whilst a 4-position boundmethylene group of an ethylene chain may be replaced by a carbonylgroup; and

C denotes a C₁₋₄ -alkylene group,

an --O--CH₂ -- or --O--CH₂ CH₂ -- group, wherein the oxygen atom isbound to a carbon atom of group B or to one of the bicyclic groupsformed by B together with A and the methylene group of the --O--CH₂ --group is bound to a carbon atom of the cyclic group of general formulaI,

a 1,4-cyclohexylene group in which a hydrogen atom in the 1-positiontogether with a hydrogen atom in the 4-position may be replaced by anethylene group,

a 1,4-phenylene group,

or C together with A and B denotes a 4-piperidinylene group in which thehydrogen atom in the 1-position together with a hydrogen atom in the4-position is replaced by a methylene or ethylene group,

or, if B is a 1,4-piperazinylene group, C may also represent a --CO--CH₂-- group, wherein the carbonyl group is bound to a nitrogen atom of the1,4-piperazinylene group of group B,

or if B denotes a bond, C may also represent a 1,4-piperidinylene groupin which the nitrogen atom is linked to the group A, or a1,2,3,4-tetrahydro-2,6-naphthylene group which is linked in the2-position to the group A);

a second of the groups R_(a) to R_(d) denotes a group of the formula

    F--E--D--

(wherein D denotes a C₁₋₄ -alkylene group,

a 1,3- or 1,4-phenylene group optionally substituted by a fluorine orchlorine atom or by a methyl, trifluoromethyl or cyano group,

a 1,4-cyclohexylene group in which a hydrogen atom in the 1-positiontogether with a hydrogen atom in the 4-position may be replaced by anethylene group,

a 1,5-indanylene, 2,6-naphthylene or 1,2,3,4-tetrahydro-2,6-naphthylenegroup,

or, if E is a 1,4-piperidinylene group, D may also represent a --CO--CH₂-- group, in which the carbonyl group is linked to the nitrogen atom ofthe 1,4-piperidinylene group of group E,

E denotes a bond,

a --CH═CH-- group,

a C₁₋₄ -alkylene group which may be substituted by a C₁₋₄ -alkyl group,by a phenyl group or by a C₁₋₄ -alkylsulphonylamino group,

an --O--CH₂ -- group, wherein the oxygen atom is linked to the group D,

a 1,4-cyclohexylene group,

or, if D is a --COCH₂ -- group, E may also represent a1,4-piperidinylene group, wherein the nitrogen atom is linked to thecarbonyl gruop of the --COCH₂ -- group of group D; and

F denotes a carbonyl group which is substituted by a hydroxy group, by aC₁₋₅ -alkoxy group, by a phenylalkoxy group having 1 to 3 carbon atomsin the alkoxy moiety, or by an R₇ O-- group, wherein

R₇ denotes a C₅₋₇ -cycloalkyl group or a cyclohexylmethyl or indanylgroup,

or F denotes an R₈ CO--O--CHR₉ --CO--, phosphono, O-methyl-phosphono orO-ethyl-phosphono group, wherein

R₈ denotes a cycloalkyloxy group having 5 to 7 carbon atoms in thecycloalkyl moiety, or a C₁₋₄ -alkyl or C₁₋₄ -alkoxy group, and

R₉ denotes a hydrogen atom or a methyl group,

and the shortest distance between group F and the furthest removednitrogen atom of the group A--B--C-- amounts to at least 11 bonds;)

a third of the groups R_(a) to R_(d) denotes a hydrogen atom or amethyl, trifluoromethyl or phenyl group; and

the fourth of the groups R_(a) to R₄ denotes a hydrogen atom or a methylgroup;

and each carbon atom in the above mentioned alkylene and cycloalkylenemoieties is linked to at most one heteroatom;

the tautomers, stereoisomers and salts thereof.

The most particularly preferred compounds of general formula I are, withthe exception of

1-(4-amidino-phenyl)-3-4-(2-phosphono-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-butyloxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

2-(4-amidino-phenyl)-4-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

1-(4-amidino-phenyl)-3-4-(2-ethoxycarbonyl-ethyl)-phenyl!-3H-imidazol-2-one,

2-(4-amidino-phenyl)-4-4-(2-isobutyloxycarbonyl-ethyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

1-(4-aminomethyl-phenyl)-3-3-(2-carboxy-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-aminomethyl-phenyl)-3-3-(2-methoxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-4-methyl-3H-imidazol-2-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-imidazolidin-2-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-3H-imidazol-2-one,

1-(4-amidino-phenyl)-3-4-(2-isopropyloxycarbonyl-ethyl)-phenyl!-imidazolidin-2,4-dione and

2-(4-amidino-phenyl)-4-4-(2-phosphono-ethyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

and with the proviso that at least one of conditions (i) to (viii) belowmust be satisfied

(i) X denotes a carbimino group substituted by a cyano group at. thenitrogen atom,

(ii) Y denotes a 1,2-cyclohexylene group,

(iii) A denotes an amidino group substituted by an R₁ --CO--O--(R₂CR₃)--O--CO-- group,

(iv) B denotes a 1,4-azacycloheptylene group, a 1,4-piperidinylene groupoptionally substituted by 1 to 4 methyl groups and which mayadditionally be substituted in the 4-position by a cyano oraminocarbonyl group, a 1,4-piperazinylene group, or

A and B together denote a 2-amino-ethoxy or 4-quinuclidinyl group,

(v) C denotes a 1,4-piperidinylene, 1,2,3,4-tetrahydro-2,6-naphthyleneor 1,4-bicyclo 2.2.2!octanylene group,

(vi) D denotes a 1,3-phenylene, cis-1,4-cyclohexylene ortrans-1,4-cyclohexylene group,

(vii) E denotes a straight-chained C₂₋₄ -alkylene chain which issubstituted by a C₁₋₄ -alkyl group, by a phenyl group, or by a C₁₋₄-alkylsulphonylamino group, or

a 1,4-piperidinylene group,

(viii) F denotes an alkoxycarbonyl group having a total of 3 to 6 carbonatoms, an R₇ --CO--, R₈ CO--O--CHR₉ --O--CO--, phosphono or.O-ethyl-phosphono group;

wherein:

X denotes a carbimino group substituted by a cyano group at the nitrogenatom, or a carbonyl or sulphonyl group,

Y denotes a CH₂ CH₂, CH₂ CH₂ CH₂ or CH═CH group optionally substitutedby R_(c) or by R_(c) and R_(d),

an N═CH group optionally substituted by R_(c),

a CH₂ CO or COCH₂ group,

a 1,2-phenylene or 1,2-cyclohexylene group, wherein

R_(c) denotes a hydrogen atom or a methyl, trifluoromethyl or phenylgroup and

R_(d) denotes a hydrogen atom or a methyl group,

R_(a) denotes a group of the formula

    A--B--C--

(wherein A denotes an amidino group optionally substituted by an R₁--CO--O--(R₂ CR₃)--O--CO-- group, wherein

R₁ denotes a methyl group,

R₂ denotes a hydrogen atom or a methyl group and

R₃ denotes a hydrogen atom,

or A denotes an aminomethyl group or, if A is bound to a nitrogen atomof groups B or C, A may also denote a hydrogen atom or a methyl group;

B denotes a bond, a 1,4-azacycloheptylene group, a 1,4-piperidinylenegroup optionally substituted by 1 to 4 methyl groups and which mayadditionally be substituted in the 4-position by a cyano oraminocarbonyl group, or a 1,4-piperazinylene group, wherein a nitrogenatom of the above mentioned groups is linked to the group A, or

A and B together denote a 2-amino-ethoxy or 4-quinuclidinyl group; and

C denotes a CH₂ CH₂ group, a 1,4-phenylene, 1,4-cyclohexylene or1,4-bicyclo 2.2.2!octanylene group,

or if B is a bond, C may also represent a 1,4-piperidinylene group whichis bound to the group A via a nitrogen atom, or a1,2,3,4-tetrahydro-2,6-napthalene group which is bound in the 2-positionto the group A,

or, if B is a 1,4-piperazinylene group, C may also represent a --COCH₂-- group linked via the carbonyl group to the 1,4-piperazinylene Bgroup);

R_(b) denotes a group of the formula

    F--E--D--

(wherein D denotes a straight-chained C₁₋₄ -alkylene group, a1,3-phenylene, or a 1,4-cyclohexylene group or a 1,4-phenylene groupoptionally substituted by a fluorine atom, or by a methyl,trifluoromethyl or cyano group, or D may denote a 2,6-naphthylene or1,2,3,4-tetrahydro-2,6-naphthylene group, or if E is a1,4-piperidinylene group, D may also represent a --COCH₂ -- group linkedvia the carbonyl group to the 1,4-piperidinylene group of group E;

E denotes a bond, a CH═CH group, a straight-chained C₂₋₄ -alkylene groupoptionally substituted by a C₁₋₄ -alkyl group, by a phenyl group or by aC₁₋₄ -alkylsulphonylamino group, or E may denote a --O--CH₂ -- group, inwhich the oxygen atom is attached to the group D, or if D is a --COCH₂-- group, E may also represent a 1,4-piperidinylene group, wherein thenitrogen atom is linked to the carbonyl group of the --COCH₂ -- group ofgroup D; and

F denotes a carbonyl group which is substituted by a hydroxy group, by aC₁₋₅ -alkoxy group or by an R₇ O-- group, wherein

R₇ denotes a cyclopentyl, cyclohexyl, cyclohexylmethyl or 5-indanylgroup,

or F denotes an R₈ CO--O--CHR₉ --O--CO--, phosphono or O-ethyl-phosphonogroup, wherein

R₈ denotes a tert.butyl, ethoxy or cyclohexyloxy group and

R₈ denotes a hydrogen atom or a methyl group,

and the shortest distance between the group F and the furthest removednitrogen atom of the group A--B--C-- amounts to at least 11 bonds);

the tautomers thereof, the stereoisomers thereof and the salts thereof.

The following are examples of particularly preferred cyclic ureaderivatives of general formula I:

(a) 2-(4-amidinophenyl)-4-4-(2-carboxy-1-propyl)phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

(b) 4- 4-(2-carboxyethyl)phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one,

(c) 1- 4-(2-carboxyethyl)phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one

(d) 4- 4-(2-carboxy-1-pentyl)phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one,

(e) 1-(4-amidinophenyl)-3- 4-2-(n-butylsulfonylamino)-2-carboxy-ethyl!phenyl!-imidazolidin-2-one,

(f) 2-(4-amidinophenyl)-4-trans-4-(2-carboxyethyl)cyclohexyl!-4H-1,2,4-triazol-3-one,

(g) 2-(4-amidinophenyl)-4- 4-2-(cyclohexyloxycarbonyl)-ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one,

(h) 2-(4-amidinophenyl)-4-trans-4-(2-carboxyethyl)cyclohexyl!-5-methyl-4H-1,2,4-triazol-3-one,

(i) 1-(4-amidinophenyl)-3-trans-4-(2-carboxyethyl)cyclohexyl!-imidazolidin-2-one,

(j) 1-(4-amidinophenyl)-3-trans-4-(2-carboxyethyl)cyclohexyl!-imidazolidin-2,4-dione,

(k) 1-(4-amidinophenyl)-3- trans-4-2-(methoxycarbonyl)-ethyl)cyclohexyl!-imidazolidin-2-one,

(l) 1-(trans-4-carboxycyclohexyl)-3-4-(4-cyano-4-piperidinyl)phenyl!-imidazolidin-2-one,

(m) 1-4-(4-aminocarbonyl-4-piperidinyl)phenyl!-3-(trans-4-carboxycyclohexyl)-imidazolidin-2-one,

(n) 1- 4- 2-(ethoxycarbonyl)ethyl!phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one,

(o) 1-(trans-4-carboxycyclohexyl)-3-4-(4-piperidinyl)-phenyl!-imidazolidin-2-one,

(p) 1- trans-4-(2-carboxyethyl)cyclohexyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one,

(q) 1- 4-(2-carboxyethyl)phenyl!-3-2-(4-quinuclidinyl)-ethyl)-imidazolidin-2-one,

(r) 1-(2-(4-quinuclidinyl)ethyl!-3-(4-2-(ethoxycarbonyl)-ethyl!phenyl!-imidazolidin-2-one,

(s) 1- trans-4-(5-indanyloxycarbonyl)cyclohexyl!-3-4-(4-piperidinyl)phenyl!-imidazolidin-2-one,

(t) 1- trans-4-1-(cyclohexyloxycarbonyloxy)ethyl!oxycarbonyl!cyclohexyl!-3-4-(4-piperidinyl)phenyl!-imidazolidin-2-one,

(u) 1- trans-4-(ethoxycarbonyl)cyclohexyl!-3-4-(4-piperidinyl)phenyl!-imidazolidin-2-one,

(v) 1- trans-4- 2-(ethoxycarbonyl)ethyl!cyclohexyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one,

(w)1-(2-aminomethyl-1,2,3,4-tetrahydro-6-naphthyl)-3-(trans-4-carboxycyclohexyl)-imidazolidin-2-one,

(x) 1- trans-4- (carboxymethyl)oxy!cyclohexyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one,

(y) 1- 4-(2-carboxyethenyl)-2-fluoro-phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one,

(z) 1-(trans-4-carboxycyclohexyl)-3-4-(4-piperidinyl)cyclohexyl!-imidazolidin-2-one,

(aa) 1-(trans-4-carboxycyclohexyl)-3-4-(4-quinuclidinyl)-phenyl!-imidazolidin-2-one,

(bb) 1-(trans-4-caboxycyclohexyl)-3-4-(4-methyl-4-piperidinyl)phenyl!-imidazolidin-2-one,

(cc) 1- 4-(4-quinuclidinyl)phenyl!-3-trans-4-(ethoxycarbonyl)cyclohexyl!-imidazolidin-2-one,

(dd) 1- trans-4-(ethoxycarbonyl)cyclohexyl!-3-4-(4-methyl-4-piperidinyl)phenyl!-imidazolidin-2-one,

(ee) 1- 4-(2-carboxyethenyl)phenyl!-3-2-(4-piperidinyl)-ethyl!-imidazolidin-2-one,

(ff) 1- trans-4-(ethoxycarbonyl)cyclohexyl!-3-4-(4-piperidinyl)phenyl!-3H-imidazol-2-one,

(gg) 1- 4-aminomethyl)-bicyclo 2.2.2!octan-1-yl!-3-4-(2-carboxyethyl)phenyl!-imidazolidin-2-one,

(hh) 1- 4-(2-carboxy-1-phenyl-ethyl)phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one,

(ii) 1-(2-carboxy-1,2,3,4-tetrahydro-6-naphthyl)-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one and

(jj) 1-(trans-4-carboxycyclohexyl)-3- 4-(2-aminoethyl)oxy!-phenyl!imidazolidin-2-one,

the stereoisomers thereof and the salts thereof.

The new compounds may be prepared by the following processes, forexample:

a) in order to prepare compounds of general formula I wherein A is ashereinbefore defined and F denotes a carboxy group or F has the meaningsgiven hereinbefore with the exception of the carboxy group and A denotesa C₁₋₅ -aminoalkyl group, an amino, amidino or guanidino group, whereinat one of the nitrogen atoms in each of the above mentioned groups oneor two hydrogen atoms may each be replaced by an alkyl group, or, if Ais bound to a nitrogen atom of groups B or C which is not part of alactam group, A represents a hydrogen atom:

converting a compound of general formula ##STR3## wherein R_(a), R_(b),X and Y are as hereinbefore defined, with the proviso that one of thegroups R_(a) to R_(d) denotes an F'--E--D-- group and one other of thegroups R_(a) to R_(d) denotes an A--B--C-- group or one of the groupsR_(a) to R_(d) denotes an F--E--D-- group and one other of the groupsR_(a) to R_(d) denotes an A'--B--C-- group or one of the groups R_(a) toR_(d) denotes an F'--E--D-- group and one other of the groups denotes anA'--B--C-- group, wherein

A to F are as hereinbefore defined,

A' denotes a group which may be converted by hydrolysis, treatment withacid, thermolysis or hydrogenolysis into an aminoalkyl, amino, amidinoor guanidino group, whilst at one of the nitrogen atoms in each of theabove mentioned groups, one or two hydrogen atoms may each be replacedby an alkyl group, or, if A' is bound to a nitrogen atom of groups B orC which is not part of a lactam group, A' may denote a group which maybe replaced by a hydrogen atom by hydrolysis, treatment with acid,thermolysis or hydrogenolysis and

F' denotes a group which may be converted into a carboxy group byhydrolysis, treatment with acid, thermolysis or hydrogenolysis,

into a compound of general formula I wherein A is as hereinbeforedefined and F denotes a carboxy group or F has the meanings givenhereinbefore with the exception of the carboxy group and A denotes anaminoalkyl group having 1 to 5 carbon atoms, an amino, amidino orguanidino group, in which at one of the nitrogen atoms in each of theabove mentioned groups, one or two hydrogen atoms may each be replacedby an alkyl group, or, if A is bound to a nitrogen atom of groups B or Cwhich is not part of a lactam group, A may also represent a hydrogenatom.

For example, functional derivatives of the carboxyl group such asunsubstituted or substituted amides, esters, thioesters,trimethylsilylesters, orthoesters, iminoesters, amidines or anhydrides,or a nitrile group, may be converted by hydrolysis into a carboxylgroup; esters with tertiary alcohols, e.g. tert.butylesters, may beconverted by treatment with an acid or thermolysis into a carboxylgroup; and esters with aralkanols, e.g. benzylesters, may be convertedby hydrogenolysis into a carboxy group, and

by hydrolysis imino groups which are substituted by a protecting groupsuch as a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl ormethoxycarbonyl group, or by treatment with an acid or thermolysis iminogroups which are substituted by a protecting group such as atert.butyloxycarbonyl group, or by hydrogenolysis imino groups which aresubstituted by a protecting group such as a benzyloxycarbonyl, benzyl,methoxybenzyl or 2,4-dimethoxybenzyl group,

are converted into the corresponding NH compound.

The hydrolysis is appropriately carried out either in the presence of anacid such as hydrochloric acid, sulphuric acid, phosphoric acid, aceticacid, trichloroacetic acid or trifluoroacetic acid, or mixtures thereof,or in the presence of a base such as lithium hydroxide, sodium hydroxideor potassium hydroxide, in a suitable solvent such as water,water/methanol, water/ethanol, water/isopropanol, methanol, ethanol,water/tetrahydrofuran or water/dioxane, at temperatures between -10° C.and 120° C., e.g. at temperatures between ambient temperature and theboiling temperature of the reaction mixture.

If F' in a compound of formula II represents a cyano or aminocarbonylgroup, these groups may also be converted into a carboxyl group with anitrite, e.g. sodium nitrite, in the presence of an acid such assulphuric acid, which may appropriately be used as the solvent at thesame time, at temperatures between 0° and 50° C.

If, in a compound according to Formula II, A' contains or denotes F',for example the tert.butyloxycarbonyl group, the tert.butyl group mayalso be cleaved by treatment with an acid such as trifluoroacetic acid,formic acid, p-toluenesulphonic acid, sulphuric acid, hydrochloric acid,phosphoric acid or polyphosphoric acid, optionally in an inert solventsuch as lmethylene chloride, chloroform, benzene, toluene, diethylether,tetrahydrofuran or dioxane, preferably at temperatures between -10° and120° C., e.g. at temperatures between 0° and 60° C., or it may also becleaved thermolytically, optionally in an inert solvent such asmethylene chloride, chloroform, benzene, toluene, tetrahydrofuran ordioxane and preferably in the presence of a catalytic amount of an acidsuch as p-toluenesulphonic acid, sulphuric acid, phosphoric acid orpolyphosphoric acid, preferably at the boiling temperature of thesolvent used, e.g. at temperatures between 40° and 120° C., whereby anN-carboxy-imino compound which may be formed in the reaction mixture maybe simultaneously decarboxylated.

If F' in a compound of formula II represents, for example, abenzyloxycarbonyl group, or if A' contains it, the benzyl group may alsobe hydrogenolytically cleaved in the presence of a hydrogenationcatalyst such as palladium/charcoal, in a suitable solvent such asmethanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate,dioxane or dimethylformamide, preferably at temperatures between 0° and80° C., e.g. at ambient temperature, under a hydrogen pressure of 1 to 5bar, whilst any N-carboxy-imino compound thus obtained in the reactionmixture is simultaneously decarboxylated.

b) In order to prepare compounds of general formula I wherein Arepresents an H₂ N--C(═NH)-- group in which a nitrogen atom may besubstituted by one or two C₁₋₃ -alkyl groups:

reacting a compound of general formula ##STR4## optionally formed in thereaction mixture, wherein R_(a), R_(b), X and Y are as hereinbeforedefined, with the proviso that one of the groups R_(a) to R_(d)represents a group of the formula

    Z.sub.1 --C(═NH)--B--C--

(wherein B and C are as hereinbefore defined and Z₁ denotes an alkoxy orarylkoxy group such as a methoxy, ethoxy, n-propoxy, isopropoxy orbenzyloxy group or an alkylthio or aralkylthio group such as amethylthio, ethylthio, n-propylthio or benzylthio group or an aminogroup) with an amine of general formula

    R.sub.12 --NH--R.sub.13                                    (IV)

(wherein R₁₂ and R₁₃, which may be identical or different, representhydrogen atoms or C₁₋₃ -alkyl groups) or with the addition saltsthereof.

The reaction is expediently carried out in a solvent such as methanol,ethanol, n-propanol, water, methanol/water, tetrahydrofuran or dioxaneat temperatures between -10° and 150° C., preferably at temperaturesbetween 0° and 120° C., with a corresponding free amine or with acorresponding acid addition salt such as, for example, the correspondingammonium carbonates, acetates or chlorides.

A compound of general formula III may be obtained, for example, byreacting a corresponding nitrile with a suitable alcohol such asmethanol, ethanol, n-propanol, isopropanol or benzyl alcohol in thepresence of an acid such as hydrochloric acid or by reacting acorresponding amide with a trialkyloxonium salt such astriethyloxonium-tetrafluoroborate, in a solvent such as methylenechloride, tetrahydrofuran or dioxane, at temperatures between -10° and50° C., but preferably at 0° to 30° C., or by reacting a correspondingnitrile with hydrogen sulphide, appropriately in a solvent such aspyridine or dimethylformamide and in the presence of a base such astriethylamine with subsequent alkylation of the resulting thioamide witha suitable alkyl or aralkyl halide, or by reacting a correspondingnitrile with an alkoxide such as sodium methoxide in a solvent such asdioxane or tetrahydrofuran, but preferably in the alcohol in question.During the reactions with an alcohol, any ester group present may betransesterified at the same time.

c) In order to prepare 4H-1,2,4-triazol-3-ones of general formula I:

cyclising a compound of general formula

    (R.sub.14 CZ.sub.2)═N--NR.sub.15 --CO--HN--R.sub.16    (V)

wherein

R₁₄ has the meanings given for R_(c) or R_(d) hereinbefore,

one of the groups R₁₅ or R₁₆ has the meanings given for R_(a)hereinbefore and

the other group R₁₅ or R₁₆ has the meanings given for R_(b) hereinbeforeand

Z₂ denotes. a nucleophilic leaving group such as a halogen atom, ahydroxy, alkoxy, alkylsulphenyl, amino, alkylamino or dialklylaminogroup, e.g. a chlorine, bromine or iodine atom or a methoxy, ethoxy ormethylsulphenyl group.

The reaction is optionally carried out in a solvent such as toluene,xylene, decalin, dioxane, dimethylformamide, methylenechloride,methanol, ethanol, isopropanol, pyridine, acetic acid or trifluoroaceticacid, at temperatures between 20° and 250° C., optionally in thepresence of a base or an acid such as trifluoroacetic acid or adehydrating agent such as phosphorusoxychloride, phosphoruspentachlorideor N,N'-dicyclohexylcarbodiimide. However, the reaction is preferablycarried out without a solvent.

If Z₂ denotes a halogen atom, the reaction is optionally carried out inone of the above mentioned solvents, preferably in the presence of abase such as potassium carbonate, sodium hydride, potassiumtert.butoxide or triethylamine, at temperatures between 20° and 60° C.,or if Z₂ denotes a hydroxy, alkoxy, alkylsulphenyl, amino, alkylamino ordialkylamino group, the reaction is optionally carried out in thepresence of an acid such as trifluoroacetic acid, which maysimultaneously be used as solvent, at temperatures between 20° and 120°C., but preferably without a solvent at temperatures between 100° and220° C.

d) In order to prepare compounds of general formula I wherein X denotesa carbonyl group and Y denotes one of the above mentioned ethylene orvinylene groups:

cyclising a compound of general formula

    R.sub.17 --CO--CHR.sub.18 --NR.sub.15 --CO--NHR.sub.16     (VI)

optionally formed in the reaction mixture, wherein

one of the groups R₁₅ or R₁₆ has the meanings given for R_(a)hereinbefore and

the other group R₁₅ or R₁₆ has the meanings given for R_(b)hereinbefore,

one of the groups R₁₇ or R₁₈ has the meanings given for R_(c)hereinbefore, and

the other group R₁₇ or R₁₈ has the meanings given for R_(d)hereinbefore, optionally with subsequent hydrogenation.

The cyclisation is preferably carried out in a solvent such as methylenechloride, chloroform, acetic acid, benzene, toluene or dioxane,optionally in the presence of an acid such as trifluoroacetic acid,p-toluenesulphonic acid or hydrochloric acid and optionally in thepresence of a dehydrating agent such as phosphorusoxychloride,phosphoruspentachloride or N,N'-dicyclohexylcarbodiimide at temperaturesbetween 20° and 150° C., preferably at temperatures between 20° C. andthe boiling temperature of the solvent used.

The optional subsequent hydrogenation is preferably carried out withhydrogen in the presence of a catalyst such as palladium/charcoal orplatinum in a solvent such as methanol, ethanol, ethylacetate or glacialacetic acid, optionally with the addition of an acid such ashydrochloric acid at temperatures between 0° and 50° C., but preferablyat ambient temperature, under a hydrogen pressure of 1 to 7 bar, butpreferably 3 to 5 bar.

e) In order to prepare compounds of general formula I wherein X denotesa carbonyl group and Y denotes one of the above mentioned ethylene orvinylene groups:

Reacting a compound of general formula

    R.sub.15 --NH--CHR.sub.18 --R.sub.17 C(OR.sub.19).sub.2    (VII)

with an isocyanate of general formula

    O═C═N--R.sub.16                                    (VIII)

wherein one of the groups R₁₅ or R₁₆ has the meanings given for R_(a)hereinbefore and

the other group R₁₅ or R₁₆ has the meanings given for R_(b)hereinbefore,

one of the groups R17 or R₁₈ has the meanings given for R_(c)hereinbefore and

the other group R₁₇ or R₁₈ has the meanings given for R_(d) hereinbeforeand

R₁₉ denotes a C₁₋₄ alkyl group, optionally with subsequenthydrogenation.

The reaction is optionally carried out in an inert solvent such asdioxane or toluene at temperatures between 20° and 200° C., preferablyat temperatures between 20° and 160° C. However, the reaction may alsobe carried out without a solvent.

An open-chained urea optionally obtained as intermediate product in thereaction of a compound of general formula VII and with an isocyanate ofgeneral formula VIII is subsequently, if desired, converted into thedesired compound in the presence of an acid such as acetic acid,trifluoroacetic acid, p-toluenesulphonic acid or hydrochloric acid.

The optional subsequent hydrogenation is preferably carried out withhydrogen in the presence of a catalyst such as palladium/charcoal orplatinum in a solvent such as methanol, ethanol, ethyl acetate orglacial acetic acid, optionally with the addition of an acid such ashydrochloric acid at temperatures between 0° and 50° C., but preferablyat ambient temperature, under a hydrogen pressure of 1 to 7 bar,preferably 3 to 5 bar.

f) In order to prepare compounds of general formula I wherein X denotesa carbonyl group and Y denotes one of the above mentioned COCH₂, CH₂ CO,CONH or NHCO groups:

Cyclising a compound of general formula ##STR5## wherein R_(a) and R_(b)are as hereinbefore defined, one of the groups U₁ or U₂ represents ahydrogen atom and the other group U₁ or U₂ represents either a Z₃--CO--CH₂ -- group optionally substituted by R_(c) or R_(d) or by R_(c)and R_(d), wherein

Z₃ represents a nucleophilic leaving group such as a halogen atom, ahydroxy, alkoxy or sulphonyloxy group, e.g. a chlorine, bromine oriodine atom or a methoxy, ethoxy, isopropyloxy, methanesulphonyloxy orp-toluenesulphonyloxy group,

or a Z₃ '--CONH-- group optionally substituted by R_(c) or R_(d),wherein

Z₃ ' denotes a nucleophilic leaving group such as a halogen atom or analkoxy group, e.g. a chlorine or bromine atom or a methoxy group, or

Z₃ ' together with the hydrogen atom of the NH group denotes a furthercarbon-nitrogen bond.

The reaction is optionally carried out in a solvent such as ethanol,isopropanol, methylenechloride, dioxane, toluene, dimethylformamide ordimethylsulphoxide, optionally in the presence of a base such aspyridine, triethylamine, sodium hydride or potassium tert.butoxide andoptionally in the presence of a dehydrating agent such asN,N'-dicyclohexylcarbodiimide at temperatures between 20° and 200° C.However, the reaction may also be carried out without a solvent.

If Z₃ or Z₃ ' represents a nucleophilic leaving group such as a halogenatom or a sulphoneester group, the reaction is preferably carried out inthe presence of a base such as potassium carbonate, sodium hydride,potassium tert.butoxide, pyridine or triethylamine at temperaturesbetween 20° and 60° C., if Z₃ or Z₃ ' denotes an alkoxy group, thereaction is preferably carried out without a solvent at temperaturesbetween 50° and 250° C., or if Z₃ denotes a hydroxy group, the reactionis preferably carried out in the presence of a dehydrating agent such astriphenylphosphine/carbon tetrachloride, N,N'-dicyclohexylcarbodiimideor N,N'-carbonyldiimidazole.

g) In order to prepare compounds of general formula I wherein A denotesan amino, aminoalkyl, amidino or guanidino group substituted by analkoxycarbonyl group, by a benzyloxycarbonyl group or by an R₁--CO--O(R₂ CR₃)--O--CO-- group, or A denotes an R₁ --CO--O--(R₂CR₃)--O--CO-- group:

Reacting a compound of general formula ##STR6## (wherein R_(a), R_(b), Xand Y are as hereinbefore defined, with the proviso that one of thegroups R_(a) to R_(d) denotes an A"--B--C-- group wherein

B and C are as hereinbefore defined and A" denotes an H₂ N--C₁₋₅ -alkyl,H₂ N--C(═NH)-- or H₂ N--C(═NH)--NH-- or H₂ N group or a hydrogen atom)

with a compound of general formula

    Z.sub.4 --R.sub.20                                         (XI)

wherein R₂₀ denotes an alkoxycarbonyl group having a total of 2 to 5carbon atoms, an R₁ --CO--O--(R₂ CR₃)--O--CO-- or benzyloxycarbonylgroup and

Z₄ denotes a nucleophilic leaving group such as a halogen atom, anaryloxy, arylthio, alkoxycarbonyloxy, aralkoxycarbonyloxy orN-imidazolyl group, e.g. a chlorine or bromine atom or a4-nitrophenoxygroup.

The acylation is appropriately carried out in a solvent such astetrahydrofuran, methylenechloride, chloroform, dimethylformamide, wateror mixtures of these solvents, optionally in the presence of a base suchas sodium carbonate, potassium carbonate or sodium hydroxide solution,or in the presence of a tertiary organic base such as triethylamine,N-ethyl-diisopropylamine, N-methyl-morpholine or pyridine, which maysimultaneously be used as solvent, at temperatures between -30° and 100°C., but preferably at temperatures between -10° and 60° C.

h) In order to prepare compounds of general formula I wherein F denotesa carbonyl group substituted by a C₁₋₆ -alkoxy group, by a phenylalkoxygroup or by an R₇ 0-- group:

Reacting a compound of general formula ##STR7## (wherein R_(a), R_(b), Xand Y are as hereinbefore defined, with the proviso that one of thegroups R_(a) to R_(d) represents an F"--E--D-- group wherein

E and D are as hereinbefore defined and F" denotes a carboxy oralkoxycarbonyl group)

with an alcohol of general formula

    HO--R.sub.21                                               (XIII)

wherein R₂₁ has the meanings given for R₇ hereinbefore or represents aC₁₋₆ -alkyl group or a phenylalkyl group.

The reaction of a carboxy compound is optionally carried out in asolvent or mixture of solvents such as methylene chloride,dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or dioxane or, particularly advantageously, in acorresponding alcohol of general formula XIII, optionally in thepresence of an acid such as hydrochloric acid or in the presence of adehydrating agent, e.g. in the presence of isobutyl chloroformate,thionylchloride, trimethylchlorosilane, sulphuric acid, methanesulphonicacid, p-toluenesulphonic acid, phosphorus trichloride, phosphoruspentoxide, N,N'-dicyclohexylcarbodiimide,N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or1-hydroxybenzotriazole and optionally also in the presence of4-dimethylamino-pyridine, N,N'-carbonyldiimidazole ortriphenylphosphine/carbon tetrachloride, conveniently at temperaturesbetween 0° and 150° C., preferably at temperatures between 0° and 80° C.

The reaction of a corresponding alkoxycarbonyl compound with an alcoholof general formula XIII is preferably carried out in a suitable alcoholas solvent, optionally in the presence of another solvent such asmethylene chloride or ether, preferably in the presence of an acid suchas hydrochloric acid, at temperatures between 0° and 150° C., preferablyat temperatures between 50° and 100° C.

i) In order to prepare compounds of general formula I wherein A denotesan H₂ N--CH₂ --V-- group, where V denotes a bond or a straight-chainedor branched C₁₋₄ -alkylene group:

Reduction of a compound of general formula ##STR8## wherein R_(a),R_(b), X and Y are as hereinbefore defined, with the proviso that one ofthe groups R_(a) to R_(d) denotes an NC--V--B--C-- group, wherein

B and C are as hereinbefore defined and V denotes a bond or astraight-chained or branched C₁₋₄ -alkylene group.

The reduction is preferably carried out in a suitable solvent such asmethanol, methanol/water, methanol/water/ammonia, ethanol, ether,tetrahydrofuran, dioxane or dimethylformamide, optionally with theaddition of an acid such as hydrochloric acid, in the presence ofcatalytically activated hydrogen, e.g. hydrogen in the presence ofRaney-Nickel, platinum or palladium/charcoal, or in the presence of ametal hydride such as sodium borohydride, lithium borohydride or lithiumaluminium hydride, at temperatures between 0° and 100° C., preferably attemperatures between 20° and 80° C.

j) In order to prepare compounds of general formula I wherein A denotesan aminoalkyl group in which the amino group is not bound to aquaternary carbon atom, or A denotes an amino group which is bound to aCH or CH₂ group of the group B or C:

Reduction of a compound of general formula ##STR9## wherein R_(a),R_(b), X and Y are as hereinbefore defined, with the proviso that one ofthe groups Rato R_(d) denotes an A--B--C-- group wherein

A, B and C are as hereinbefore defined, with the proviso that an H₂N--CH or H₂ N--CH₂ group present in group A, in group A and B together,or in group A and C together, is replaced by an HO--N═C< or HO--N═CH--group.

The reduction is preferably carried out in a suitable solvent such asmethanol, methanol/water, methanol/water/ammonia, ethanol, ether,tetrahydrofuran, dioxane or dimethylformamide, optionally with theaddition of an acid such as hydrochloric acid in the presence ofcatalytically activated hydrogen, e.g. hydrogen in the presence ofRaney-nickel, platinum or palladium/charcoal, at temperatures between 0°and 100° C., preferably at temperatures between 0° and 100° C.

k) In order to prepare compounds of general formula I wherein X denotesa carbimino group substituted by a cyano group, or a carbonyl,thiocarbonyl or sulphonyl group:

Reacting a compound of general formula

    R.sub.a --NH--Y'--NH--R.sub.b                              (XVI)

(wherein R_(a) and R_(b) are as hereinbefore defined and

Y' represents a straight-chained C₂₋₃ -alkylene group optionallysubstituted by R_(c) or R_(d) or by R_(c) and R_(d), whilst a methylenegroup in such an ethylene group may additionally be substituted by acarbonyl group, or

Y' denotes a CO--NH, NH--CO, CH═N or N═CH group optionally substitutedby R_(c) or R_(d)) with a compound of general formula

    Z.sub.5 --X'--Z.sub.6                                      (XVII)

wherein

X' denotes a carbimino group substituted by a cyano group, or

X' denotes a carbonyl, thiocarbonyl or sulphonyl group,

Z₅ and Z₆, which may be identical or different, represent nucleophilicleaving groups such as halogen atoms, alkoxy or aryloxy groups, e.g. achlorine atom or a methoxy, ethoxy, phenyloxy or N-imidazolyl group.

The reaction is preferably carried out in a solvent such as methylenechloride, chloroform, toluene or dioxane, optionally in the presence ofa base such as sodium hydride, triethylamine or pyridine, attemperatures between 0° and 100° C., preferably at temperatures between20° and 60° C.

l) In order to prepare compounds of general formula I wherein X denotesa carbimino group substituted by a cyano group, or X denotes a carbonylor sulphonyl group and Y represents a straight-chained C₂₋₃ -alkylenegroup optionally substituted by R_(c) or R_(d) or by R_(c) and R_(d) :

Cyclising a compound of general formula ##STR10## wherein R_(a) andR_(b) are as hereinbefore defined,

X" denotes a cyano-substituted carbimino group or a carbonyl orsulphonyl group,

one of the groups U₃ or U₄ represents a hydrogen atom and

the other group U₃ or U₄ represents a straight-chained C₂₋₃ -alkylenegroup optionally substituted by R_(c) or R_(d) or by R_(c) and R_(d),and which may also be terminally substituted by a nucleophilic leavinggroup such as a halogen atom, a hydroxy or sulphonic acid ester group,e.g. by a chlorine, bromine or iodine atom or by a methanesulphonyloxyor p-toluenesulphonyloxy group.

The reaction is preferably carried out in a solvent such as methylenechloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide ordimethylsulphoxide, optionally in the presence of a base such as sodiumhydride, potassium carbonate, potassium tert.butoxide orN-ethyl-diisopropylamine and optionally in the presence of a dehydratingagent such as triphenylphosphine/diethyl azodicarboxylate attemperatures between -20° and 100° C., preferably at temperaturesbetween 0° and 60° C.

m) In order to prepare compounds of general formula I wherein X denotesa carbonyl or sulphonyl group:

Reacting a compound of general formula ##STR11## with a compound ofgeneral formula

    Z.sub.7 --R.sub.16                                         (XX)

wherein Y is as hereinbefore defined

X' denotes a cyano-substituted carbimino group or a carbonyl orsulphonyl group,

one of the groups R₁₅ or R₁₆ has the meanings given for R_(a)hereinbefore and

the other group R₁₅ or R₁₆ has the meanings given for R_(b) hereinbeforeand

Z₇ denotes a nucleophilic leaving group such as a halogen atom, ahydroxy or sulphonic acid ester group, e.g, a fluorine, chlorine,bromine or iodine atom or a methanesulphonyloxy or p-toluenesulphonyloxygroup.

The reaction is preferably carried out in a solvent such as methylenechloride, acetonitrile, tetrahydrofuran, toluene, pyridine,dimethylformamide, dimethylsulphoxide or N-methyl-pyrrolidone,optionally in the presence of a base such as sodium hydride, potassiumcarbonate, potassium tert.butoxide, N-ethyl-diisopropylamine orN,N,N',N'-tetramethyl-ethylenediamine and optionally in the presence ofa dehydrating agent such as triphenylphosphine/diethyl azodicarboxylateand optionally in the presence of copper powder or a copper salt such ascopper(I) iodide as reaction accelerator, at temperatures between -20°and 220° C., but preferably at temperatures between 0° and 60° C. if Z₇is bound to an aliphatic carbon atom, or at temperatures between 60° and180° C. if Z₇ is bound to an aromatic carbon atom, whilst in this caseZ₇ can only represent a halogen atom.

n) In order to prepare compounds of general formula I wherein A denotesan alkyl group:

Reacting a compound of general formula ##STR12## (wherein R_(a), R_(b),X and Y are as hereinbefore defined, with the proviso that one of thegroups R_(a) to R_(d) denotes an A"'--B--C-- group wherein

B and C are as hereinbefore defined and

A"' denotes a hydrogen atom)

with a compound of general formula

    Z.sub.8 --R.sub.22                                         (XXII)

wherein

R₂₂ denotes a C₁₋₃ -alkyl group and Z₈ denotes a nucleophilic leavinggroup such as a halogen atom, e.g. a chlorine, bromine or iodine atom,or a sulphonic acid ester group, e.g. a methanesulphonyloxy orp-toluenesulphonyloxy group, or

Z₈ together with an adjacent hydrogen atom of the group R₂₂ representsan oxygen atom.

The alkylation-with a compound of formula XXII, wherein Z₈ denotes anucleophilic leaving group, is appropriately carried out in a solventsuch as methylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxideor dimethylformamide, optionally in the presence of a base such assodium carbonate, potassium carbonate or sodium hydroxide solution or inthe presence of a tertiary organic base such as N-ethyl-diisopropylamineor N-methyl-morpholine, which may simultaneously be used as solvents, attemperatures between -30° and 100° C., but preferably at temperaturesbetween -10° and 80° C.

The reductive alkylation with a carbonyl compound of general formulaXXII is carried out in the presence of a complex metal hydride such assodium borohydride, lithium borohydride or sodium cyanoborohydride,conveniently at a pH of 6 to 7 and at ambient temperature or in thepresence of a hydrogenation catalyst, e.g. with hydrogen in the presenceof palladium/charcoal, at a hydrogen pressure of 1 to 5 bar. However,methylation is preferably carried out in the presence of formic acid asa reducing agent at elevated temperatures, e.g. at temperatures between60° and 120° C.

o) In order to prepare compounds of general formula I wherein at leastone of the groups B, C, D or E denotes a cyclohexylene group optionallysubstituted by an alkyl group:

Hydrogenation of a compound of general formula ##STR13## wherein R_(a),R_(b), X and Y are as hereinbefore defined, with the proviso that atleast one of the groups B, C, D or E denotes a phenylene groupoptionally substituted by an alkyl group.

The catalytic hydrogenation is preferably carried out in a suitablesolvent such as methanol, methanol/water, acetic acid, ethyl acetate,ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide,optionally with the addition of an acid such as hydrochloric acid, inthe presence of catalytically activated hydrogen, e.g. hydrogen in thepresence of Raney-nickel, platinum, rhodium or palladium/charcoal, attemperatures between 0° and 100° C., preferably at temperatures between20° and 80° C.

p) In order to prepare compounds of general formula I wherein A denotesa cyano group, B denotes a bond and C is an optionally alkyl-substituted4 to 7 membered cycloalkylene group or B denotes an optionallyalkyl-substituted cyclohexylene group:

Reacting a compound of general formula ##STR14## (wherein R_(a), R_(b),X and Y are as hereinbefore defined, with the proviso that one of thegroups R_(a) to R_(d) denotes an A--B--C-- group wherein A together witha CH group in one of the 4 to 7 membered cycloalkyl groups mentioned forB or C hereinbefore denotes a carbonyl group) with a compound of generalformula

    Z.sub.9 --CH.sub.2 --NC                                    (XXV)

wherein Z₉ denotes a nucleophilic leaving group such as ap-toluenesulphonyl group.

The reaction is preferably carried out in a solvent such astetrahydrofuran, ethyleneglycol dimethylether, tert.butanol orethyleneglycol dimethylether/tert.butanol in the presence of a base suchas potassium tert.butoxide at temperatures between -25° and 50° C.,preferably at temperatures between -20° C. and ambient temperature.

q) In order to prepare compounds of general formula I wherein F denotesa carbonyl group substituted by a C₁₋₆ -alkoxy group, or by aphenylalkoxy or R₈ --CO--O--CHR₉ --O-- group:

Reacting a compound of general formula ##STR15## (wherein R_(a), R_(b),X and Y are as hereinbefore defined, with the proviso that one of thegroups R_(a) to R_(d) denotes an F"'--E--D-- group wherein

E and D are as hereinbefore defined and

F"' denotes a carboxyl group)

with a compound of general formula

    Z.sub.10 --R.sub.23                                        (XXVII)

wherein

R₂₃ denotes a C₁₋₆ -alkyl group, a phenylalkyl or R₈ --CO--O--CHR₉ --group, wherein R₈ and R₉ are as hereinbefore defined, and

Z₁₀ denotes a nucleophilic leaving group such as a halogen atom or asulphonic acid ester group, e.g. a chlorine or bromine atom or amethanesulphonyloxy or p-toluenesulphonyloxy group.

The reaction is preferably carried out in a solvent such asmethylenechloride, tetrahydrofuran, dioxane, dimethylsulphoxide ordimethylformamide, optionally in the presence of a reaction acceleratorsuch as sodium or potassium iodide and preferably in the presence of abase such as sodium carbonate, potassium carbonate or sodium hydroxidesolution or in the presence of a tertiary organic base such asN-ethyl-diisopropylamine or N-methyl-morpholine, which maysimultaneously also serve as solvent, or optionally in the presence ofsilver carbonate or silver oxide at temperatures between -30° and 100°C., but preferably at temperatures between -10 and 80° C.

r) In order to prepare compounds of general formula I, in which Atogether with B is a cyanoalkoxy group with 1 to 10 carbon atoms in thealkoxy moiety, which is bound to a carbon atom of group C via an oxygenatom:

reaction of a compound of general formula ##STR16## (wherein R_(a),R_(b), X and Y are as hereinbefore defined, with the proviso that one ofgroups R_(a) to R_(d) is a HO--C group in which the hydroxy group isbound to a carbon atom of the group C) with a compound of generalformula

    Z.sub.11 --R.sub.24                                        (XXIX)

in which

R₂₄ denotes a cyanoalkyl group with 1 to 10 carbon atoms in the alkylmoiety and

Z₁₁ denotes a nucleophilic leaving group such as a halogen atom, e.g. achlorine, bromine or iodine atom, or a sulphonate group, e.g. amethanesulphonyloxy or p-toluenesulphonyloxy group.

The reaction is appropriately carried out in a solvent such as methylenechloride, tetrahydrofuran, dioxane, dimethylsulphoxide ordimethylformamide preferably in the presence of a base such as sodiumcarbonate, potassium carbonate or sodium hydroxide solution or in thepresence of a tertiary organic base such as N-ethyl-diisopropylamine orN-methyl-morpholine, which may also serve simultaneously as the solvent,at temperatures between -30° and 100° C., preferably however attemperatures between -10° and 80° C.

If according to the invention a compound of general formula I isobtained which contains a cyano group, this may be converted into anaminocarbonyl or carboxy group by treating with an aqueous acid or base,

a compound of general formula I, which contains a double bond betweentwo carbon atoms, may be converted to a corresponding saturated compoundby reduction. The subsequent conversion of a cyano group into anaminocarbonyl group is preferably carried out in sulphuric acid in thepresence of water or with sodium carbonate or potassium carbonate in thepresence of aqueous hydrogen peroxide solution, optionally using asolvent such as dimethylsulphoxide, but preferably in 85% sulphuric acidat ambient temperature.

The subsequent conversion of a cyano group into a carboxy group isconveniently carried out with aqueous sulphuric acid or sodium orpotassium hydroxide solution at elevated temperatures, but preferablywith aqueous sulphuric acid at temperatures between 80° C. and theboiling temperature of the reaction mixture.

The subsequent reduction of a carbon-carbon double bond is preferablyeffected by catalytic hydrogenation in a suitable solvent such asmethanol, methanol/water, acetic acid, ethyl acetate, ethanol, ether,tetrahydrofuran, dioxane or dimethylformamide, optionally with theaddition of an acid such as hydrochloric acid, in the presence ofcatalytically activated hydrogen, e.g. hydrogen in the presence ofRaney-nickel, platinum, rhodium or palladium/charcoal, or in thepresence of a hydrogen donor such as 1,3-cyclohexadiene or ammoniumformate in the presence of a catalyst such as palladium/charcoal,platinum oxide or Raney-nickel in a solvent such as methanol, ethanol,water, dioxane, acetic acid or ethyl acetate, at temperatures between 0°and 100° C., preferably at temperatures between 20° and 80° C.

In the reaction described hereinbefore, any reactive groups present suchas hydroxy, carboxy, phosphono, O-alkylphosphono, amino, alkylamino,imino or amidino groups may optionally be protected during the reactionby means of conventional protecting groups which are cleaved again afterthe reaction.

For example, the protective group for a hydroxy group may be atrimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl ortetrahydropyranyl group,

the protecting group for a carboxyl group may be a trimethylsilyl,methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group,

the protecting groups for a phosphono group may be an alkyl group suchas methyl, ethyl, isopropyl or n-butyl group or a phenyl or benzylgroup,

the protecting group for an optionally alkyl-substituted amidino groupmay be a benzyloxycarbonyl group,

the protecting group for an amino, alkylamino or imino group may be aformyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl,benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groupand for the amino group a phthalyl group may also be considered, and

the protecting group for the nitrogen atom of a 1-aza-bicycloalkylgroup, such as the quinuclidinyl group, may be the benzyl group orborane.

The optional subsequent cleaving of a protecting group may, for example,be carried out hydrolytically in an aqueous solvent, e.g. in water,isopropanol/water, acetic acid/water, tetrahydrofuran/water ordioxane/water, in the presence of an acid such as trifluoroacetic acid,hydrochloric acid or sulphuric acid, or in the presence of an alkalimetal base such as sodium hydroxide or potassium hydroxide, oraprotically, e.g. in the presence of iodotrimethylsilane, attemperatures between 0° and 120° C., preferably at temperatures between10° and 100° C.

However a benzyl, methoxybenzyl or benzyloxycarbonyl group may becleaved hydrogenolytically, for example, using hydrogen in the presenceof a catalyst such as palladium/charcoal in a solvent such as methanol,ethanol, ethyl acetate or glacial acetic acid, optionally with theaddition of an acid such as hydrochloric acid, at temperatures between0° and 100° C., but preferably at temperatures from 20° to 60° C., undera hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar. However, a2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acidin the presence of anisole.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acid,or by treating with iodotrimethylsilane, optionally using a solvent suchas methylene chloride, dioxane, methanol or ether.

A trifluoroacetyl group is preferably cleaved by treating with an acidsuch as hydrochloric acid, optionally in the presence of a solvent suchas acetic acid, at temperatures between 50° and 120° C., or by treatingwith sodium hydroxide solution, optionally in the presence of a solventsuch as tetrahydrofuran, at temperatures between 0° and 50° C.

A phthalyl group is preferably cleaved in the presence of hydrazine or aprimary amine such as methylamine, ethylamine or n-butylamine, in asolvent such as methanol, ethanol, isopropanol, toluene/water ordioxane, at temperatures between 20° and 50° C.

The cleaving of the complex of a 1-aza-bicycloalkyl group such as thequinuclidinyl group, with borane is preferably carried out by treatingwith an acid such as hydrochloric acid and optionally in the presence ofa solvent such as methanol, ethanol, acetic acid or dioxane, attemperatures between 0° C. and the boiling temperature of the reactionmixture. During this reaction, any ester group present maysimultaneously be converted into the corresponding carboxy group.

The cleaving of only an alkyl group from an O,O'-dialkylphosphono groupis carried out, for example, with sodium iodide in a solvent such asacetone, ethylmethylketone, acetonitrile or dimethylformamide, attemperatures between 40° and 150° C., but preferably at temperaturesbetween 60° and 100° C.

The cleaving of both alkyl groups from an O,O-dialkylphosphono group iscarried out, for example, with iodotrimethylsilane, bromotrimethylsilaneor chlorotrimethylsilane/sodium iodide in a solvent such as methylenechloride, chloroform or acetonitrile, at temperatures between 0° C. andthe boiling temperature of the reaction mixture, but preferably attemperatures between 20° and 60° C.

Furthermore, the compounds of general formula I obtained may be resolvedinto their enantiomers and/or diastereomers as mentioned hereinbefore.Thus, for example, cis/trans mixtures may be resolved into their cis andtrans isomers, and compounds having at least one optically active carbonatom may be resolved into their enantiomers.

Thus, for example, the cis/trans mixtures obtained may be resolved bychromatography into the cis and trans isomers thereof and the compoundsof general formula I which occur in racemate form may be separated bymethods known per se (cf. Allinger N. L. and Eliel E. L. in "Topics inStereochemistry", Vol. 6, Wiley Interscience, 1971) into their opticalantipodes, and compounds of general formula I having at least 2asymmetric carbon atoms may be separated on the basis of theirphysical-chemical differences using known methods, e.g. bychromatography and/or fractional crystallisation, into the diastereomersthereof which, if they occur in recemic form, may subsequently beseparated into the enantiomers as mentioned above.

The separation of enantiomers is preferably effected by columnseparation on chiral phases or by recrystallisation from an opticallyactive solvent or by reacting with optically active substances,especially acids or activated derivatives thereof or alcohols, whichform salts or derivatives thereof such as for example, esters or amideswith the racemic compound, and separation of the diastereomeric saltmixture or derivative thus obtained, e.g. on the basis of theirdifferent solubilities, whilst the free antipodes may be released fromthe pure diastereomeric salts or derivatives by the action of suitableagents. Particularly common, optically active acids include, forexample, the D- and L-forms of tartaric acid and malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, aspartic acid and quinicacid. The optically active alcohol may be (+) or (-)-menthol, forexample, and the optically active acyl group in amides may be, forexample, (+)- or (-)-menthyloxycarbonyl.

Moreover, the compounds of formula I obtained may be converted into thesalts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts thereof with inorganic or organicacids. Examples of suitable acids include hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid,lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the new compounds of formula I thus obtained, if theycontained a carboxyl, phosphono, O-alkylphosphono or 5-tetrazolyl group,may subsequently, if desired, be converted into the addition saltsthereof with inorganic or organic bases, more particularly, forpharmaceutical use, into the physiologically acceptable addition saltsthereof. Examples of suitable bases include sodium hydroxide, potassiumhydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine andtriethanolamine.

The compounds used as starting materials are known from the literaturein some cases or may be obtained by methods known from the literature,as described in the Examples.

Thus, for example, in "The Organic Chemistry of Heterocyclic Compounds",Volume 37, by C. Temple, Jr., published by John Wiley & Sons, 1981,Chapters 13, 14 and 19 describe the preparation of correspondingtriazole compounds.

In Houben-Weyl, "Methoden der Organischen Chemie", Volume E4, by H.Hagemann, published by Georg Thieme, 1983, there is a descriptionstarting on page 368 of the preparation of corresponding cyclic ureacompounds. The same volume, from page 355, also describes, for example,the preparation of corresponding open-chained urea compounds which maybe required as starting compounds.

Thus, for example, a corresponding cyclic urea derivative is obtained bycyclising a correspondingly substituted urea, which is in turn obtainedby reacting a corresponding amine with a suitable isocyanate, or byreacting a correspondingly substituted diamine with a carbonic acidderivative such as phosgene or

a corresponding triazalone derivative is obtained by cyclising acorresponding semicarbazide, which is in turn obtained by reacting acorresponding isocyanate with a suitable hydrazide.

In the resulting cyclic urea derivatives, a carbonyl group maysubsequently, if desired, be converted into a corresponding thiocarbonylor-carbimino group using known methods.

In the resulting cyclic starting compounds or in the starting compoundsrequired for the preparation thereof,

any ester group present may optionally be converted by hydrolysis into acarboxy group,

any carboxy group present may be converted into an ester or amide group,

any aminocarbonyl group present may be converted by dehydration into acyano group,

any cyano group present may be converted into an amidino group,

any carbonyl group present may be converted into the oxime thereof,

any functional group present such as a hydroxy, amino or 5-tetrazolylgroup may be converted by alkylation, sulphonylation, acylation ortritylation into the corresponding derivative,

any cyano group present may be converted into a tetrazolyl group or

any reactive bromine atom present may be converted by means of a metalcyanide into a cyano group.

As already mentioned hereinbefore, the new cyclic urea derivatives ofgeneral formula I and the salts thereof,

particularly the physiologically acceptable salts thereof, withinorganic or organic acids or bases, have valuable properties. Thus, thenew compounds of general formula I wherein A, A together with B, Atogether with C, or A together with B and C contains a basic group or agroup which may optionally be converted in vivo into a basic group, andF denotes a carboxyl, phosphono, O-alkylphosphono or 5-tetrazolyl groupor a group which can optionally be converted in vivo into a carboxyl,phosphono, O-alkylphosphono or 5-tetrazolyl group, e.g. a carbonyl groupsubstituted by an alkoxy or cycloalkoxy group, have valuablepharmacological properties, in addition to having an inhibitory effecton inflammation and bone degradation, they have in particularantithrombotic, antiaggregatory and tumour- or metastases-inhibitingeffects.

The compounds of general formula I wherein A represents a cyano orcyanoalkyl group are valuable intermediates in the preparation of thecorresponding aminoalkyl and amidino compounds of general formula I.Moreover, the compounds of general formula I wherein A denotes a benzylgroup optionally substituted in the phenyl moiety by 1 to 2 methoxygroups, or A denotes a formyl, acetyl, trifluoroacetyl,benzyloxycarbonyl or alkoxycarbonyl group, are valuable intermediatesfor preparing the corresponding imino compounds of general formula Iwherein A denotes a hydrogen atom.

Furthermore, compounds of general formula I wherein A together with B,or A together with B and C represent an azabicycloalkyl group complexedby borane at the nitrogen atom or quaternised by a benzyl groupoptionally substituted by 1 or 2 methoxy groups in the phenyl nucleus,are valuable intermediate products for preparing the correspondingcompounds of general formula I which are not complexed at the nitrogenatom and not quaternised.

By way of example, the compounds of general formula I were investigatedfor their biological effects as follows:

1. Inhibition of Binding of ³ H-BIBU 52 to Human Thrombocytes

A suspension of human thrombocytes in plasma is incubated with ³ H-BIBU52 =(3S,5S)-5- (4'-amidino-4-biphenylyl)oxymethyl!-3-(carboxyl)methyl!-2-pyrrolidinone ³ -³ H-4-biphenylyl!! (see the GermanPatent application P 42 14 245.8 by the same applicant dated 30.04.1992,internal reference: Case 5/1-93-FL), which replaces the ligand ¹²⁵I-fibrinogen known from the literature and various concentrations of thesubstance to be tested. The free and bound ligand is separated bycentrifuging and quantitatively determined by scintillation counting.From the measurements obtained, the inhibition of ³ H-BIBU 52 binding bythe test substance is determined.

In order to do this, donor blood is taken from an anticubital vein andanticoagulated by trisodium citrate (final concentration 13 mM). Theblood is centrifuged for 10 minutes at 170×g and the supernatantplatelet-rich plasma (PRP) is removed. The remaining blood is vigorouslycentrifuged once more in order to obtain plasma. The PRP is diluted 1:10with autologous plasma. 750 μl are incubated with 50 μl of physiologicalsaline solution, 100 μl of test substance solution, 50 μl of ⁴ C-sucrose(3,700 Bq) and 50 μl of ³ H-BIBU 52 (final concentration: 5 nM) atambient temperature for 20 minutes. In order to measure non-specificbinding, instead of the test substance, 5 μl of BIBU 52 are put in(final concentration: 30 μM). The samples are centrifuged for 20 secondsat 10,000×g and the supernatant is drawn off. 100 μl therof are measuredin order to determine the free ligand. The pellet is dissolved in 500 μlof 0.2N NaOH, 450 μl are mixed with 2 ml of scintillator and 25 μl of 5NHCl and measured. The residual plasma remaining in the pellet isdetermined from the ¹⁴ C content, the bound ligand from the ³ Hmeasurement. After subtracting the non-specific binding, the pelletactivity is plotted against the concentration of the test substance andthe concentration for a 50% inhibition of binding is determined.

2. Antithrombotic effect:

Method

The thrombocyte aggregatrion is measured using the Born and Cross method(J. Physiol. 170: 397 (1964)) in platelet-rich plasma taken from healthvolunteers. To inhibit coagulation the blood is mixed with 3.14% sodiumcitrate in a ratio by volume of 1:10.

Collagen-induced agaregation

The pattern of the decrease in optical density of the plateletsuspension is photometrically measured and recorded after the additionof the aggregation-triggering substance. The rate of aggregation isconcluded from the angle of inclination of the density curve. The pointon the curve where there is maximum light transmittance is used tocalculate the optical density.

The amount of collagen used is as small as possible but sufficient toproduce an irreversible reaction curve. Standard commercial collagenproduced by Hormonchemie of Munich is used.

Before the addition of the collagen the plasma is incubated for 10minutes with the substance at 37° C.

From the measurements obtained an EC₅₀ is determined graphically,indicating a 50% change in the optical density in terms of theinhibition of aggregation.

The following table shows the results which were obtained:

    ______________________________________                Fibrinogen-  Inhibition of platelet    Substance   binding test aggregation    (Example No.)                IC.sub.50  nM!                             EC.sub.50  nM!    ______________________________________      1(1)      0.8          30      1(2)      1.2          70      1(3)      64.0         270      1(4)      280.0        500      1(6)      18.0         100      1(8)      760.0        1200      1(21)     1.0          36      1(39)     25.0         86      1(44)     --           380      1(50)     65.0         170      2(5)      3500.0       3200      4         94.0         130      4(4)      2.9          30      4(5)      4100.0       3300      4(13)     250.0        300      5(2)      720.0        840      6(14)     250.0        40      6(34)     21000.0      350      6(35)     5700.0       630      6(37)     7100.0       380      6(40)     2500.0       240     15         12000.0      4300     17         16.0         43     18(2)      --           110     24(1)      150.0        940     24(2)      --           71     26         26.0         84     30(4)      200.0        490    ______________________________________

Moreover, the compound of Example 6(14), for example, inhibits thecollagen-induced aggregation of thrombocytes in the rhesus monkey exvivo after the oral administration of 1 mg/kg for up to four hours.

The compounds according to the invention are well tolerated becauseafter intravenous administration of 30 mg/kg of the compounds ofExamples 1(1), 1(4), 1(6), 1(39), 17 and 26 to mice, none of the threeanimals tested died.

In the light of their inhibitory effect on cell-to-cell orcell-to-matrix interactions, the new cyclic urea derivatives of generalformula I and the physiologically acceptable addition salts thereof aresuitable for treating or preventing diseases in which smaller or greatercell aggregates occur or in which cell-to-matrix interactions play apart, e.g. in treating or preventing venous and arterial thrombosis,cerebrovascular diseases, lung embolism, cardiac infarction,arteriosclerosis, osteoporosis and the metastasis of tumours and thetreatment of genetically caused or acquired disorders of cellinteractions with one another or with solid structures. They are alsosuitable for parallel therapy in thrombolysis with fibrinolytics orvascular interventions such as transluminal angioplasty or in thetreatment of shock, psoriasis, diabetes and inflammation.

For treating or preventing the diseases mentioned above the dosage isbetween 0.1 μg and 30 mg/kg of body weight, preferably 1 μg to 15 mg/kgof body weight, given in up to 4 doses per day. For this purpose thecompounds of formula I produced according to the invention, optionallyin conjunction with other active substances, such as thromboxanereceptor antagonists and thromboxane synthesis inhibitors orcombinations thereof, serotonin antagonists, α-receptor antagonists,alkylnitrates such as glycerol trinitrate, phosphodiesterase inhibitors,prostacyclin and the analogues thereof, fibrinolytics such as tPA,prourokinase, urokinase, streptokinase, or anticoagulants such asheparin, dermatane sulphate, activated protein C, vitamin K antagonists,hirudine, inhibitors of thrombin or other activated clotting factors,may be incorporated together with one or more inert conventionalcarriers and/or diluents, e.g. with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethyleneglycol, propyleneglycol,stearylalcohol, carboxymethyl-cellulose or fatty substances such as hardfat or suitable mixtures thereof, into conventional galenic preparationssuch as plain or coated tablets, capsules, powders, suspensions,solutions, sprays or suppositories.

The Examples which follow are intended to illustrate the invention:

EXAMPLE I

1-Acetyl-2-(4-cyanophenyl)-4-4-(1-ethoxycarbonyl-2-propyl)-phenyl!-semicarbazide

2.79 g of 1-acetyl-2-(4-cyanophenyl)-hydrazine and 4.13 g of4-(1-ethoxycarbonyl-2-propyl)phenyl!isocyanate are stirred for 2 hoursat 100° C. under nitrogen. Then the mixture is cooled. The product isfurther reacted in Example 3 without any further purification.

Yield: 6.5 g (94% of theory); R_(f) value: 0.37 (Silica gel; methylenechloride/ethyl-acetate/cyclohexane=20:1:1)

The following compounds are obtained analogously to Example I:

(1) 1-acetyl-2-(4-cyanophenyl)-4-4-(2-ethoxycarbonyl-1-propyl)phenyl!-semicarbazide R_(f) value: 0.32(Silica gel; methylene chloride/ethyl-acetate=20:1)

(2) 1-acetyl-2-(4-cyanophenyl)-4- cis-4-2-(methoxy-carbonyl)-ethyl!cyclohexyl!-semicarbazide

Melting point: 138°-140° C.; R_(f) value: 0.54 (Silica gel; methylenechloride/ethyl acetate=4:1)

(3) 1-acetyl-2-(4-cyanophenyl)-4- trans-4-2-(methoxy-carbonyl)ethyl!cyclohexyl!-semicarbazide

Melting point: 132°-134° C.; R_(f) value: 0.54 (Silica gel; methylenechloride/ethyl acetate=4:1)

(4) 1-Acetyl-2-(4-cyanophenyl)-4- 3-2-(methoxy-carbonyl)-ethyl!phenyl!-semicarbazide

R_(f) value: 0.55 (Silica gel; methylene chloride/ethyl acetate=9:1)

(5) 1-trifluoroacetyl-2-(4-cyanophenyl)-4- 4-2-(methoxy-carbonyl)ethyl!phenyl!-semicarbazide

R_(f) value: 0.60 (Silica gel; methylene chloride/methanol=20:1)

(6) 1-acetyl-2-(4-cyanophenyl)-4- 4-2-(methoxy-carbonyl)-ethyl!phenyl!-semicarbazide

R_(f) value: 0.42 (Silica gel; methylene chloride/ethyl acetate=9:1)

(7) 1-benzoyl-2-(4-cyanophenyl)-4- 4-2-(methoxy-carbonyl)-ethyl!phenyl!-semicarbazide

Melting point: 76°-81° C.; R_(f) value: 0.32 (Silica gel; methylenechloride/ethyl acetate=20:1)

(8) 1-acetyl-4- 4- 2-(methoxycarbonyl)ethyl!phenyl!-semicarbazide

Melting point: 159°-165° C.; R_(f) value: 0.37 (Silica gel; Methylenechloride/Methanol=9:1)

(9) 2-(4-cyanophenyl)-1-formyl-4- trans-4-2-(methoxy-carbonyl)ethyl!cyclohexyl!-semicarbazide

Melting point: 140°-142° C.; R_(f) value: 0.57 (Silica gel; methylenechloride/ethyl acetate=4:1)

(10) 1-acetyl-4- 4- 2-(methoxycarbonyl)-1-pentyl!-phenyl!-semicarbazide

Melting point: 109°-111° C.; Calculated: C 60.88 H 7.51 N 12.53; Found:60.81 7.51 12.30

(11) 1-acetyl-4- 4-2-(methoxycarbonyl)-3-methyl-1-butyl!-phenyl!-semicarbazide

(12) 1-acetyl-4- 4- 2-(methoxycarbonyl)-1-butyl!phenyl!-semicarbazide

(13) 1-acetyl-4- 4- 2-(methoxycarbonyl)-1-propyl!-phenyl!-semicarbazide

(14) 1-acetyl-2-(4-cyanophenyl)-4- 4-2-(methoxy-carbonyl)-1-pentyl!phenyl)-semicarbazide

(15) 1-formyl-4- 4- 2-(methoxycarbonyl)ethyl!phenyl!-semicarbazide

Melting point: 146°-148° C.; R_(f) value: 0.34 (Silica gel; methylenechloride/methanol=100:5)

(16) 1-formyl-4- trans-4-(methoxycarbonyl)cyclohexyl!-semicarbazide

Melting point: 183° C.; R_(f) value: 0.48 (Silica gel; methylenechloride/methanol=5:1)

(17) 1-acetyl-4- trans-4-(methoxycarbonyl)cyclohexyl!-semicarbazide

Melting point: 191° C.; R_(f) value: 0.50 (Silica gel; methylenechloride/methanol=5:1)

EXAMPLE II

3-(4-Bromophenyl)-1- 4-(2-carboxyethyl)phenyl!-imidazolidin-2-one

12.7 g of 3-(4-bromophenyl)-1- 4-2-(ethoxycarbonyl)-ethyl!-phenyl!-imidazolidin-2-one, 300 ml oftetrahydrofuran, 100 ml of water and 23.6 ml of 4N sodium hydroxidesolution are stirred overnight at ambient temperature. The precipitateis suction filtered, suspended in 1 litre of water, acidified withconcentrated hydrochloric acid and stirred for 2 hours. It is thensuction filtered, washed with water and dried at 60° C.

Yield: 7.8 g (66% of theory); Melting point: 244°-246° C.; Calulated: C55.54 H 4.40 N 7.20 Br 20.53; Found: 55.65 4.48 7.24 20.37

EXAMPLE III

1-(4-Bromophenyl)-3- 4- 2-(ethoxycarbonyl)ethyl!phenyl!-imidazolidin-2-one

To a solution of 13.5 g of N-(4-bromophenyl)-N'- 4-2-(ethoxycarbonyl)ethyl!phenyl!-N'-(2-hydroxyethyl)-urea in 40 ml ofmethylene chloride are added 3.7 g of methane sulphonyl chloride andthen, whilst cooling in an ice/methanol bath, 3.8 g of triethylamine in10 ml of methylene chloride are added dropwise. After 1 hour's stirringwithout cooling, water is added, the phases are separated and theaqueous phase is extracted with methylene chloride. The combined organicphases are washed with water, dried and concentrated by evaporation. Theresidue is refluxed for 3 hours with 9.3 g of sodium iodide in 250 ml ofacetone. The mixture is evaporated to dryness, the residue is dissolvedin 100 ml of dimethylformamide and 3.7 g of potassium tert.butoxide in25 ml of dimethylformamide are added whilst cooling with ice. After 30minutes' stirring at ambient temperature, the mixture is evaporateddown, the residue is distributed between water and methylene chlorideand the aqueous phase is extracted with methylene chloride. The combinedorganic phases are washed with water, dried and concentrated by rotaryevaporation. The residue is stirred overnight with ethanol, cooled andthe product is suction filtered, washed with ethanol and dried.

Yield: 8.9 g (69% of theory); R_(f) value: 0.40 (Silica gel; methylenechloride); Calculated: C 57.57 H 5.07 N 6.71 Br 19.15; Found: 57.34 4.996.83 19.27

EXAMPLE IV

1- 4- 2-(Methoxycarbonyl)ethyl!phenyl!-imidazolidin-2-one

To 11.3 g of N-(2-chloroethyl)-N'- 4-2-(methoxy-carbonyl)ethyl!-phenyl!-urea in 15 ml of dimethylformamide isadded, dropwise without cooling, a solution of 4.5 g of potassiumtert.butoxide in 15 ml of dimethylformamide. After 2 hours stirring thereaction mixture is poured onto 600 ml of water. The precipitate issuction filtered, washed with water and dried at 100° C.

Yield: 8.84 g (89% of theory); Melting point: 171°-172° C.; R_(f) value:0.46 (Silica gel; methylene chloride/methanol=20:1)

The following compounds are obtained analogously to Example IV:

(1) 1- 4- 2-(methoxycarbonyl)-1-pentyl!phenyl!-imidazolidin-2-one

(2) l- 4-(1-trifluoroacetyl-4-piperidinyl)phenyl!-imidazolidin-2-one

Melting point: 198°-201° C.; R_(f) value: 0.51 (Silica gel; ethylacetate)

(3) 1-4-(4-cyano-1-trifluoroacetyl-4-piperidinyl)-phenyl!-imidazolidin-2-oneR_(f) value: 0.45 (Silica gel; cyclohexane/ethyl acetate=3:2)

(4) 1-(4-bromo-2-fluoro-phenyl)-imidazolidin-2-one

Melting point: 134°-136° C.

(5) 1-(4-bromo-2-trifluoromethyl-phenyl)-imidazolidin-2-one

Melting point: 139°-141° C.

(6) 1-(4-bromo-2-methyl-phenyl)-imidazolidin-2-one

Melting point: 184°-186° C.

(7) 1-(4- 2-(methoxycarbonyl)ethenyl!phenyl!-imidazolidin-2-one

Melting point: 233°-234° C.

(8) 1- 4- 2-(ethoxycarbonyl)-1-phenyl-ethyl!-phenyl!-imidazolidin-2-one

Melting point: 167°-169° C.

EXAMPLE V

4-2-(n-Butylsulfonylamino)-2-(methoxycarbonyl)-ethyl)!-N-(2-hydroxyethyl)-aniline

5.0 g of 4- 2-(n-butylsulfonylamino)-2-(methoxy-carbonyl)-ethyl!-anilinein 50 ml of acetonitrile are mixed with 1N hydrochloric acid until a pHof 6-7 is obtained. 1.02 g of glycolaldehyde (dimer) are dissolved inthis mixture and 1.13 g of sodium cyanoborohydride are added in batchesthereto. After 1 hours' stirring at ambient temperature the mixture isevaporated down and the residue is distributed between ice water andethyl acetate. The aqueous phase is made alkaline and extracted withethyl acetate. The combined organic phases are washed with salinesolution, dried and evaporated down. The residue is purified bychromatography over a silica gel column with cyclohexane/ethyl acetate(1:1 to 3:7).

Yield: 1.6 g (29% of theory); R_(f) value: 0.31 (Silica gel;cyclohexane/ethyl acetate=3:7)

The following compound is obtained analogously to Example V:

(1) 1-benzyl-4- (2-hydroxyethyl)amino!-piperidine

R_(f) value: 0.33 (Silica gel; methylenechloride/methanol/cyclohexane/conc. aqueous ammonia=7:1.5:1.5:0.2)

EXAMPLE VI

1-(1-Hydroxyimino-1,2,3,4-tetrahydronaphthalin-6-yl)-3- 4-2-(methoxycarbonyl)ethyl!phenyl!-imidazolidin-2-one

To a boiling solution of 2.35 g of1-(1-oxo-1,2,3,4-tetrahydronaphthalin-6-yl)-3- 4-2-(methoxycarbonyl)-ethyl!phenyl!-imidazolidin-2-one in a mixture of 100ml of methanol, 50 ml of.dioxane and 1.5 ml of pyridine, are added 460mg of hydroxylamine-hydrochloride and the mixture is refluxed for 2hours. After cooling overnight it is suction filtered, washed withmethanol, water and methanol again and dried.

Yield: 2.3 g (94% of theory); R_(f) value: 0.42 (Silica gel; methylenechloride/methanol=95:5) Calculated: C 67.80 H 6.18 N 10.31; Found: 67.706.04 10.21

EXAMPLE VII

1-(1-Oxo-1,2,3,4-tetrahydronaphthalin-6-yl)-3- 4-2-(methoxycarbonyl)ethyl!phenyl!-imidazolidin-2-one

To a solution of 3.7 g of triphenylphosphine and 5.5 g ofN-(1-oxo-1,2,3,4-tetrahydronaphthalin-6-yl)-N'-(2-hydroxyethyl)-N'- 4-2-(methoxycarbonyl)ethyl!phenyl!-urea in 40 ml acetonitrile, are added,dropwise at 40°-45° C., 2.84 g of diethyl azodicarboxylate in 10 ml ofacetonitrile. After 1.5 hours the mixture is cooled, the product issuction filtered and washed with a little acetone and diethylether.

Yield: 4.27 g (81% of theory); Melting point: 180°-182° C.; Calculated:C 70.39 H 6.16 N 7.14; Found: 70.43 6.13 7.14

The following compound is obtained analogously to Example VII:

(1) 1- 4- 2-(methoxycarbonyl)ethyl!phenyl!-4-methyl-imidazolidin-2-one

R_(f) value: 0.16 (Silica gel; cyclohexane/ethyl acetate=1:1)

EXAMPLE VIII

4- 2-(n-Butylsulfonylamino)-2-(methoxycarbonyl)-ethyl!-aniline

19 g of 4-2-(n-butylsulfonylamino)-2-(methoxycarbonyl)-ethyl!-nitrobenzene(melting point 102°-104° C.; prepared fromβ-(4-nitrophenyl)-D,L-alanine-methylester by reacting withn-butylsulfonic acid chloride in the presence ofN-ethyl-diisopropylamine) are hydrogenated in 200 ml of ethyl acetate atambient temperature under a hydrogen pressure of 3.4 bar in the presenceof 2 g of palladium on activated charcoal (10% palladium) for 1.5 hours.The catalyst is suction filtered and the filtrate is evaporated down.

Yield: 17.8 g (100% of theory); R_(f) value: 0.45 (Silica gel;cyclohexane/ethyl acetate=1:1)

The following compounds are obtained analogously to Example VIII:

(1) 4-(4-cyano-1-trifluoroacetyl-4-piperidinyl)-aniline

R_(f) value: 0.28 (Silica gel; cyclohexane/ethyl acetate=2:1)

(2) 4-(1-trifluoroacetyl-4-piperidinyl)-aniline

Melting point: 111°-112° C.; R_(f) value: 0.25 (Silica gel;cyclohexane/ethyl acetate=2:1)

(3) 2- 4- 2-(methoxycarbonyl)ethyl!phenyl!amino!-aniline

The starting material 2- 4-2-(methoxycarbonyl)-ethyl!phenyl!-amino!-nitrobenzene (melting point:68°-70° C.) is obtained by reacting 2-fluoro-nitrobenzene with methyl3-(4-aminophenyl)propionate.

R_(f) value: 0.25 (Silica gel; methylene chloride/ethyl acetate=100:1)

(4) 4- 2-(O,O'-diethylphosphono)ethyl!-aniline

The starting material 4- 2-(O,O'-diethylphosphono)-ethenyl!-nitrobenzene(melting point: 102°-104° C.) is obtained by reacting tetraethylmethanediphosphonate/potassium tert.butoxide with 4-nitrobenzaldehyde.

R_(f) value: 0.55 (Silica gel; ethyl acetate/ethanol=15:1)

(5) 4-(4-aminophenyl)-quinuclidine

Carried out in 1N hydrochloric acid, isolation of the base.

R_(f) value: 0.89 (Reversed Phase Silica gel; methanol/5% saline=6:4)

(6) 4-(4-aminophenyl)-4-methyl-1-trifluoroacetyl-piperidine

R_(f) value: 0.33 (Silica gel; cyclohexane/ethyl acetate=7:3)

(7) ethyl 3-(4-aminophenyl)-3-phenyl-propionate-hydrochloride

Carried out in ethanol in the presence of ethanolic hydrochloric acid.The starting material ethyl 3-(4-nitrophenyl)-3-phenyl-acrylate R_(f)value: 0.36 (Silica gel; cyclohexane/methylene chloride=1:1)! isobtained by reaction of 4-nitrobenzophenone with triethylphosphonoacetate.

R_(f) value: 0.40 (Reversed Phase Silica gel; methanol/5% saline=6:4)

EXAMPLE IX

4- 4- 2-(Methoxycarbonyl)ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one

8.1 g of 1-acetyl-4- 4- 2-(methoxycarbonyl)ethyl!phenyl!-semicarbazideare heated with 60 ml of 1N sodium hydroxide solution over a steam bathfor 1.5 hours. Then the mixture is cooled somewhat, filtered and thefiltrate is acidified slightly with citric acid. It is filtered and thefiltrate is mixed with concentrated hydrochloric acid. The precipitateis filtered, washed with water and dried. The intermediate product isstirred overnight in methanol with some methanolic hydrochloric acid.The reaction mixture is evaporated down and the residue is trituratedwith tert.-butyl-methylether, suction filtered and dried.

Yield: 4.98 g (65% of theory); R_(f) value: 0.40 (Silica gel;toluene/dioxane/ethanol/ethyl acetate=90:10:10:6); Calculated: C 59.76 H5.79 N 16.08; Found: 59.54 5.86 16.05

The following compounds are obtained analogously to Example IX:

(1) 4- 4-2-(methoxycarbonyl)-1-pentyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one

Melting point: 135°-137° C.; Calculated: C 63.35 H 6.98 N 13.85; Found:63.39 7.04 13.83

(2) 4- 4-2-(methoxycarbonyl)-3-methyl-1-butyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one

(3) 4- 4-2-(methoxycarbonyl)-1-butyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one

(4) 4- 4-2-(methoxycarbonyl)-1-propyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one

(5) 4- 4- 2-(methoxycarbonyl)ethyl!phenyl!-4H-1,2,4-triazol-3-one

Melting point: 174°-176° C.; R_(f) value: 0.57 (Silica gel;toluene/dioxane/ethanol/ethyl acetate=90:10:10:6)

(6) 4- trans-4-(methoxycarbonyl)cyclohexyl!-4H-1,2,4-triazol-3-one

Melting point: 204°-206° C.; Calculated: C 53.32 H 6.71 N 18.66; Found:53.29 6.66 18.83

(7) 4-trans-4-(methoxycarbonyl)cyclohexyl!-5-methyl-4H-1,2,4-triazol-3-one

Melting point: 203°-204° C.; Calculated: C 55.22 H 7.15 N 17.56; Found:55.14 7.23 17.32

Example X

1-tert.Butyloxycarbonyl-4- 2-(methanesulfonyloxy)ethyl!-piperidine

A solution of 1.3 g of1-tert.butyloxycarbonyl-4-(2-hydroxyethyl)-piperidine in 30 ml methylenechloride is mixed 710 mg of methanesulfonyl chloride and cooled in anice bath. 640 mg of triethylamine are slowly added dropwise thereto.After 1 hours' stirring, ice water is added, the mixture is stirred for15 minutes and then the organic phase is separated off and evaporateddown. The residue is stirred with a little diisopropylether andpetroleum ether, the product is suction filtered, washed with petroleumether and dried.

Yield: 1.37 g (80% of theory); Melting point: 81°-84° C.; R_(f) value:0.43 (Silica gel; cyclohexane/ethyl acetate=1:1)

The following compounds are obtained analogously to Example X:

(1) 1-tert.butyloxycarbonyl-4-2-(methanesulfonyloxy)-ethyl!-1-azacycloheptane

The 1-tert.butyloxycarbonyl-4-(2-hydroxyethyl)-1-azacycloheptane used asstarting material is obtained starting from ethyl1-aza-4-cycloheptyl-acetate by reacting with di-tert.butyl pyrocarbonateand subsequent reduction with lithium borohydride.

R_(f) value: 0.48 (Silica gel; cyclohexane/ethyl acetate=1:1)

(2) 4- 2-(methansulfonyloxy)ethyl!-quinclidine×BH₃

Melting point: 83°-86° C.; R_(f) value: 0.44 (Silica gel;cyclohexane/ethyl acetate=3:7)

(3) 1-tert.butyloxycarbonyl-3-2-(methane-sulphonyloxy)-ethyl!pyrrolidine

The starting material,1-tert.butyloxycarbonyl-3-(2-hydroxyethyl)pyrrolidine R_(f) value: 0.30(Silica gel; cyclohexane/ethyl acetate=1:1)!, is obtained by reaction of3-(2-hydroxymethyl)pyrrolidine with di-tert.butyl pyrocarbonate.

R_(f) value: 0.36 (Silica gel; cyclohexane/ethyl acetate=1:1)

EXAMPLE XI

N-(1-oxo-1,2,3,4-tetrahydronaphthalin-6-yl)-N'-(2-hydroxyethyl)-N'- 4-2-(methoxycarbonyl)ethyl!phenyl!-urea

To 4.1 g of N-(2-hydroxyethyl)-4- 2-(methoxycarbonyl) ethyl!-aniline in10 ml of dioxane are added 3.9 g of(1-oxo-1,2,3,4-tetrahydronaphthalin-6-yl)-isocyanate in 10 ml of dioxaneand the mixture is stirred overnight. The reaction mixture is evaporateddown, the residue is taken up in ethyl acetate and washed with dilutecitric acid solution and saline solution. The organic phase isevaporated down and purified by chromatography over a silica gel columnusing cyclohexane/ethyl acetate (3:7).

Yield: 5.6 g (73% of theory); R_(f) value: 0.21 (Silica gel;cyclohexane/ethyl acetate=3:7)

The following compounds are obtained analogously to Example XI:

(1) N-(2,2-diethoxyethyl)-N-(1,4-dioxaspiro 4.5!decan-8-yl)-N'- 4-2-(methoxycarbonyl)ethyl!phenyl!-urea

R_(f) value: 0.34 (Silica gel; cyclohexane/ethyl acetate=1:1)

(2) N-(4-cyanophenyl)-N'-(2-hydroxyethyl)-N'- 4-2-(methoxycarbonyl)ethyl!phenyl!-urea

Melting point: 98°-101° C.

(3) N-(4-bromophenyl)-N'- 4-2-(ethoxycarbonyl)ethyl!phenyl!-N'-(2-hydroxyethyl)-urea

R_(f) value: 0.38 (Silica gel; cyclohexane/ethyl acetate=6:4)

(4) N-(4-cyanophenyl)-N-(methoxycarbonylmethyl)-N'- trans-4-2-(methoxycarbonyl)ethyl!cyclohexyl!-urea

Melting point: 108°-110° C.; R_(f) value: 0.62 (Silica gel; methylenechloride/ethyl acetate=4:1)

(5) N-(2-chloroethyl)-N'- 4- 2-(methoxycarbonyl)ethyl!phenyl!-urea

Melting point: 124°-125° C.

(6) N-(2-chloroethyl)-N'- 4- 2-(methoxycarbonyl)-1-pentyl!-phenyl!-urea

(7) N-(1-benzyl-4-piperidinyl)-N-(2-hydroxyethyl)-N'- 4- 4-(methoxycarbonyl)butyl!phenyl!-urea

Melting point: 118°-120° C.; R_(f) value: 0.67 (Silica gel; methylenechloride/cyclohexane/methanol/conc. aqueous ammonia=7:1.5:1.5:0.2)

(8) N- trans-4-(ethoxycarbonyl)cyclohexyl!-N-(2-hydroxyethyl)-N'-4-(1-trifluoroacetyl-4-piperidinyl)phenyl!-urea

Reaction of the isocyanate with the cis/trans mixture of the aminocompound and isolation of the trans compounds by chromatography oversilica gel.

Melting point: 158°-160° C.; R_(f) value: 0.32 (Silica gel;cyclohexane/ethyl acetate=1:1)

(9) N-(2-chloroethyl)-N'-4-(1-trifluoroacetyl-4-piperidinyl)-phenyl!-urea

R_(f) value: 0.68 (Silica gel; ethyl acetate/cyclohexane=7:3)

(10) N- 4-2-(n-butylsulfonylamino)-2-(methoxycarbonyl)-ethyl!phenyl!-N'-4-(cyanophenyl)-N-(2-hydroxyethyl)-ureaR_(f) value: 0.26 (Silica gel; cyclohexane/ethyl acetate=3:7)

(11) N- 4-(ethoxycarbonyl)phenyl!-N-(2-hydroxyethyl)-N'-4-(1-trifluoroacetyl-4-piperidinyl)phenyl!-urea

Melting point: 105°-108° C.; R_(f) value: 0.23 (Silica gel;cyclohexane/ethyl acetate=1:1)

(12) N-4-(4-cyano-1-trifluoroacetyl-4-piperidinyl)-phenyl!-N'-(2-hydroxyethyl)-N'-trans-4-(methoxycarbonyl)cyclohexyl!-urea

The 4-(4-cyano-1-trifluoroacetyl-4-piperidinyl)phenyl-isocyanate used asstarting material is prepared from the corresponding amine by treatmentwith phosgene.

Melting point: from 189° C. (decomp.); R_(f) value: 0.58 (Silica gel;ethyl acetate/cyclohexane=1:1)

(13) N-(2-chloroethyl)-N'-4-4-(4-cyano-1-trifluoro-acetyl-4-piperidinyl)phenyl!-urea

R_(f) value: 0.66 (Silica gel; methylene chloride/methanol=96:4)

(14) N-(2-hydroxyethyl)-N- trans-4-(methoxycarbonyl)-cyclohexyl!-N'-4-(1-trifluoroacetyl-4-piperidinyl)-phenyl!-urea

The 4-(1-trifluoroacetyl-4-piperidinyl)phenylisocyanate used as startingmaterial is prepared from the corresponding amine by treatment withphosgene.

Melting point: 162°-163° C.; R_(f) value: 0.50 (Silica gel; ethylacetate/cyclohexane=5:1)

(15) N-2-(1-tert.butyloxycarbonyl-1-aza-4-cycloheptyl)-ethyl!-N-(2-hydroxyethyl)-N'-4- 2-(methoxycarbonyl)-ethyl!-phenyl!-urea

The N-2-(1-tert.butyloxycarbonyl-1-aza-4-cycloheptyl)-ethyl!-ethanolamine usedas amine component is obtained by reacting 1-tert.butyloxycarbonyl-4-2-(methane-sulfonyloxy)-ethyl!-1-azacycloheptane with ethanolamine.R_(f) value: 0.27 (Silica gel; cyclohexane/ethyl acetate=3:7)

(16) N- (ethoxycarbonyl)methyl!-N'- 4-2-(methoxycarbonyl)-ethyl!phenyl!-urea

Melting point: 142°-144° C.; R_(f) value: 0.71 (Silica gel;cyclohexane/ethyl acetate=2:8)

(17) N- 4- 2-(methoxycarbonyl)ethyl!phenyl!-N'-(1-hydroxy-2-propyl)-urea

Melting point: 132°-134° C.; R_(f) value: 0.42 (Silica gel; ethylacetate)

(18) N-(4-bromo-2-fluoro-phenyl)-N'-(2-chloroethyl)-urea

Melting point: 165°-167° C.

(19) N-(4-bromo-2-trifluoromethyl-phenyl)-N'-(2-chloroethyl)-urea

Melting point: 175°-177° C.

(20) N-(4-bromo-2-methyl-phenyl)-N'-(2-chloroethyl)-urea

Melting point: 180°-1820° C.

(21) N-(2-chloroethyl)-N'- 4- 2-(methoxycarbonyl)ethenyl!phenyl!-urea

R_(f) value: 0.41 (Silica gel; cyclohexane/ethyl acetate=1:1)

(22) N-(4-cyano-bicyclo 2.2.2!octan-1-yl)-N'-(2,2-dimethoxyethyl)-N'- 4-2-(methoxycarbonyl)-ethyl!phenyl-urea

The (4-cyano-bicyclo 2.2.2!octan-1-yl)isocyanate used as startingmaterial is prepared from the corresponding amine-hydrochloride byreaction with phosgene. The N- 4-2-(methoxycarbonyl)-ethyl!phenyl!aminoacetaldehyde-dimethyl acetal R_(f)value: 0.63 (Silica gel; cyclohexane/ethyl acetate=3:2)! used as aminecomponent is obtained by reaction of methyl 3-(4-aminophenyl)-propionatewith bromoacetaldehyde-dimethyl acetal in the presence ofN-ethyl-diisopropylamine.

Melting point: 93°-94° C.; R_(f) value: 0.40 (Silica gel;cyclohexane/ethyl acetate=1:1)

(23) N-(2-chloroethyl)-N'- 4-2-(ethoxycarbonyl)-1-phenyl-ethyl!phenyl!-urea

Melting point: 109°-111° C.; R_(f) value: 0.37 (Silica gel;cyclohexane/ethyl acetate=6:4)

(24) N- 2-(1-benzyl-1-azoniabicyclo2.2.2!octan-4-yl)ethyl!-N-(2,2-dimethoxyethyl)-N'- 4-2-(methoxycarbonyl)ethyl!phenyl!urea-chloride

The N- 2-(1-benzyl-1-azoniabicyclo2.2.2!-octan-4-yl)ethyl!aminoacetaldehyde-dimethylacetal-chloride-hydrochloridemelting point: 202°-204° C. (decomp.); R_(f) -value: 0.62 (ReversedPhase Silica gel, methanol/5% aqueous saline solution=6:4)!1 used asamine component is obtained by reaction of1-benzyl-4-(2-chloroethyl)-1-azoniabicyclo 2.2.2!octane-chloride withaminoacetaldehyde-dimethylacetal.

R_(f) value: 0.43 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(25) N-2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-N-(2-hydroxyethyl)-N'-2-cyano-4-2-(methoxycarbonyl)ethyl!phenyl!urea

The 2-cyano-4- 2-(methoxycarbonyl)ethyl!phenyl!-isocyanate used asstarting material is obtained by reaction of the corresponding aminewith phosgene.

R_(f) value: 0.36 (Silica gel; ethyl acetate/cyclohexane=2:1)

EXAMPLE XII

1-(4-Cyanophenyl)-3- 4-2-(N-trityl-5-tetrazolyl)ethyl!-phenyl!-imidazolidin-2-one

Under nitrogen, 0.9 g of 1-(4-bromophenyl)-3- 4-2-(N-trityl-5-tetrazolyl)ethyl!phenyl!-imidazolidin-2-one, 140 mg ofpotassium cyanide, 62 mg of palladium(II)-acetate, 142 mg oftriphenylphosphine, 18 mg of calcium hydroxide and 7 ml of drydimethylformamide are stirred for 1 hour at 100° C.

After cooling, ice water is added and the mixture is extracted severaltimes with ethyl acetate. The combined organic phases are washed withsaline solution, dried and evaporated down. The residue is purified bychromatography over a silica gel column using cyclohexane/ethyl acetate(1:1).

Yield: 270 mg (32% of theory); Melting point: 192°-194° C. (decomp.);R_(f) value: 0.65 (Silica gel; cyclohexane/ethyl acetate=3:7)

EXAMPLE XIII

1-(4-Bromophenyl)-3- 4-2-(N-trityl-5-tetrazolyl)ethyl!phenyl!-imidazolidin-2-one

To 3.1 g of 1-(4-bromophenyl)-3- 4-2-(5-tetrazolyl)-ethyl!phenyl!-imidazolidin-2-one in 80 ml of methylenechloride are added 0.91 g of triethylamine and 2.51 g of tritylchlorideand the mixture is stirred for 1.5 hours at ambient temperature. Thereaction mixture is washed with water, the organic phase is separatedoff, dried and evaporated down. The residue is briefly boiled with 70 mlof ethyl acetate, cooled somewhat and the product is suction filtered,washed with ethyl acetate and dried.

Yield: 3 .38 g (68% of theory); Melting point: 194°-197° C. (decomp.);R_(f) value: 0.67 (Silica gel; cyclohexane/ethyl acetate=1:1)

EXAMPLE XIV

1-(4-Bromophenyl)-3- 4- 2-(5-tetrazolyl)ethyl!phenyl!-imidazolidin-2-one

7.12 g of 1-(4-bromophenyl)-3- 4-2-(2-cyanoethyl)phenyl)-imidazolidin-2-one and 7.7 g of tributyltinazide are stirred in 33 ml of dimethylformamide for 9 hours at 120°-130°C. A further 3 g of tributyltin azide are added and the mixture isheated for a further 50 hours. The reaction mixture is poured onto icewater and the mixture is stirred. The precipitate is suction filtered,washed with methanol and taken up in methylene chloride. This solutionis washed with potassium fluoride solution, the organic phase isseparated off, dried and evaporated down. The residue is purified bychromatography over a silica gel column with methylene chloride/methanol(95:5). The product is stirred again with methanol, suction filtered anddried.

Yield: 4.15 g (52% of theory); Melting point: 232°-236° C. (decomp.);R_(f) value: 0.29 (Silica gel; methylene chloride/methanol=95:5)

EXAMPLE XV

1-(4-Bromophenyl)-3- 4-(2-cyanoethyl)phenyl!-imidazolidin-2-one

To 750 mg of 1-(4-bromophenyl)-3- 4-2-(aminocarbonyl)-ethyl!-phenyl!-imidazolidin-2-one and 320 mg ofpyridine in 10 ml of tetrahydrofuran are added dropwise at -10° C., withstirring, 460 mg of trifluoroacetic acid anhydride in 1 ml oftetrahydrofuran. After stirring overnight at ambient temperature thereaction mixture is diluted with ice water and the precipitate obtainedis suction filtered, washed and dried.

Yield: 700 mg (98% of theory); Melting point: 188°-192° C.

EXAMPLE XVI

3-4-(2-(Methoxycarbonyl)ethyl!phenyl!-1-(4-oxocyclohexyl)-3H-imidazol-2-on

To a solution of 12.8 g of N-(2,2-diethoxyethyl)-N-(1,4-dioxa-spiro4.5!decan-8-yl)-N'- 4- 2-(methoxy-carbonyl)ethyl!-phenyl!-urea in 20 mlof dioxane are added 5.6 ml of 3N hydrochloric acid and the mixture isstirred overnight at ambient temperature. The reaction mixture isevaporated down and the residue is distributed between methylenechloride and water. The aqueous phase is separated off and extractedwith methylene chloride. The combined organic phases are washed withwater, dried and evaporated down. The residue is purified bychromatography over a silica gel column using cyclohexane/ethyl acetate(35:65).

Yield: 2.3 g (25% of theory); Melting point: 113°-115° C.; R_(f) value:0.25 (Silica gel; cyclohexane/ethyl acetate=25:75)

EXAMPLE XVII

1- 4-(2-(Aminocarbonyl)ethyl!phenyl!-3-(4-bromophenyl)imidazolidin-2-one

9.2 g of 3-(4-bromophenyl)-1-4-(2-carboxyethyl)phenyl!imidazolidin-2-one are mixed with 3.8 g ofN,N'-carbonyldiimidazole in a mixture of 50 ml of tetrahydrofuran and 25ml of dimethylformamide and the resulting mixture is stirred for 2.5hours at 80° C. After cooling, it is poured onto a mixture of 20 ml ofconcentrated aqueous ammonia and loog-of ice and stirred for 15 minutes.The product is suction filtered and dried.

Yield: 8.8 g (97% of theory); Melting point: 248°-253° C.

EXAMPLE XVIII

4-(4-Cyano-1-trifluoroacetyl-4-piperidinyl)-nitrobenzene

To 1.6 g of 4-cyano-4-phenyl-1-trifluoroacetyl-piperidine (prepared byreacting 4-cyano-4-phenyl-piperidine with trifluoroacetic acid anhydridein the presence of N-ethyl-diisopropylamine) in 5 ml of conc. sulfuricacid, with cooling in an ice/acetone cooling bath, are added dropwise590 mg of potassium nitrate dissolved in 5 ml of conc. sulfuric acid.After 1.5 hours stirring at ambient temperature the mixture is pouredonto ice, the precipitate is suction filtered, dissolved in ethylacetate and the ethyl acetate solution is washed with water and salinesolution, then dried and evaporated down. The residue is stirred withtert.butylmethylether, suction filtered and washed withtert.butylmethylether.

Yield: 500 mg (26% of theory); Melting point: 135°-138° C.

The following compounds are obtained analogously to Example XVIII

(1) 4-(1-trifluoroacetyl-4-piperidinyl)-nitrobenzene The nitration iscarried out in glacial acetic acid/acetic anhydride with fuming nitricacid.

Melting point: 96°-100° C.; R_(f) value: 0.50 (Silica gel,cyclohexane/ethyl acetate=2:1).

(2) 4-(4-nitrophenyl)-quinuclidine

Melting point: 130°-135° C.; R_(f) value: 0.38 (Silica gel; methylenechloride/methanol/conc. aqueous ammonia=9:1:0.3)

(3) 4-methyl-4-(4-nitrophenyl)-1-trifluoroacetyl-piperidine

The nitration is carried out in glacial acetic acid/acetic anhydridewith fuming nitric acid. The starting material R_(f) value: 0.72 (Silicagel; cyclohexane/ethyl acetate=2:1)! is obtained by reaction of4-methyl-4-phenyl-piperidine with trifluoroacetic acid anhydride in thepresence of N-ethyl-diisopropylamine.

R_(f) value: 0.52 (Silica gel; cyclohexane/ethyl acetate=7:3).

EXAMPLE XIX

Methyl trans-4- (2-hydroxyethyl)amino!-cyclohexanecarboxylate

13 g of methyl trans-4-N-benzyl-N-(2-hydroxyethyl)amino!-cyclohexanecarboxylate arehydrogenated in 150 ml of methanol with 3.5 g of palladium on activatedcharcoal (10% palladium) under a hydrogen pressure of 50 psi for 20minutes at 50° C. The catalyst is suction filtered and the filtrate isevaporated to dryness. (The starting material is obtained from methyltrans-4-amino-cyclohexanecarboxylate by reacting with benzaldehyde andhydrogen in the presence of Raney-nickel and subsequently reacting with2-bromoethanol in the presence of N-ethyl-diisopropylamine).

Yield: 8.3 g (93% of theory); Melting point: 66°-68° C. R_(f) value:0.60 (Silica gel, methylene chloride/methanol/conc. aqueousammonia=4:1:0.2).

The following compounds are obtained analogously to Example XIX:

(1) methyl trans-4- (2,2-diethoxyethyl)amino!-cyclohexanecarboxylate

The starting material is obtained by reacting methyltrans-4-amino-cyclohexanecarboxylate with benzaldehyde and hydrogen inthe presence of Raney-nickel and subsequently reacting withbromoacetaldehyde-diethylacetal in the presence ofN-ethyl-diisopropylamine.

R_(f) value: 0.65 (Silica gel; methylene chloride/methanol/conc. aqueousammonia=9:1:0.1)

(2) 4-methyl-4-phenyl-piperidine

The debenzylation is carried out in the presence of palladiumhydrochloride on charcoal.

R_(f) value: 0.60 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(3) 1-(4-hydroxyphenyl)-3-trans-4-(methoxycarbonyl)cyclohexyl!-imidazolidin-2-one

Carried out in dioxane.

The starting material, 1- 4-(benzyloxy)phenyl!-3-trans-4-(methoxycarbonyl)cyclohexyl!-3H-imidazol-2-one melting point:183°-185° C., R_(f) value=0.49; (Silica gel; cyclohexane/ethylacetate=1:1)!, is obtained by treating N-4-(benzyloxy)phenyl!-N'-(2,2-diethoxyethyl)-N'-trans-4-(methoxycarbonyl)cyclohexyl!-urea with trifluoroacetic acid inmethylene chloride at ambient temperature.

Melting point: 184°-186 ° C. R_(f) value: 0.26 (Silica gel;cyclohexane/ethyl acetate=1:1)

(4) tert.butyl (trans-4-aminocyclohexyl)-oxyacetate

The starting material, tert.butyltrans-4(-dibenzylamino)cyclohexyl!-oxyacetate R_(f) value: 0.51; (Silicagel; cyclohexane/ethyl acetate=4:1)!, is obtained by reactingtrans-4-(dibenzylamino)cyclo-hexanol with tert.butyl bromoacetate intoluene/50% sodium hydroxide solution in the presence oftetrabutylammonium-hydrogen sulphate.

R_(f) value: 0.56 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

EXAMPLE XX

N- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-N'- 4-2-(n-butylsulfonylamino)-2-(methoxycarbonyl)-ethyl!-phenyl!-N-(2-hydroxyethyl)-urea

3.25 g of N,N'-carbonyldiimidazole and 2.3 g of imidazole are dissolvedin 60 ml of tetrahydrofuran and cooled to 0° C. under nitrogen. 6.15 gof 4- 2-(n-butylsulfonylamino)-2-(methoxycarbonyl)-ethyl!-aniline in 30ml of tetrahydrofuran are rapidly added dropwise with stirring and themixture is stirred for a further 4 minutes with cooling. Then 6 g of N-2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-ethanolamine (preparedby reacting 1-tert.butyloxycarbonyl-4-2-(methanesulfonyloxy)ethyl!-piperidine with ethanolamine) in 30 ml oftetrahydrofuran are added dropwise. After stirring overnight at ambienttemperature the mixture is evaporated down, taken up intert.butyl-methylether and washed with dilute citric acid and salinesolution. The organic phase is dried, concentrated by evaporation andthe residue is purified by chromatography over a silica gel column.

Yield: 1.6 g (13% of theory); R_(f) value: 0.31 (Silica gel; methylenechloride/methanol=95:5).

The following compounds are obtained analogously to Example XX:

(1) N-2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-N-(2-hydroxyethyl)-N'-4-2-(O,O'-diethylphosphono)ethyl!phenyl!-urea

R_(f) value: 0.28 (Silica gel; ethyl acetate/methanol=15:1).

(2) N-(2-cyano-1,2,3,4-tetrahydro-6-naphthyl)-N'-(2,2-diethoxyethyl)-N'-trans-4-(methoxycarbonyl)cyclohexyl!-urea

R_(f) value: 0.55 (Silica gel; cyclohexane/ethyl acetate=1:1).

(3) N-2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-N-(2,2-dimethoxyethyl)-N'-(2-methoxycarbonyl-6-naphthyl)-urea

The N-2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-aminoacetaldehyde-dimethylacetalused as starting material is obtained by reacting1-tert.butyloxy-carbonyl-4- 2-(methanesulphonyloxy)ethyl!-piperidinewith aminoacetaldehydedimethylacetal.

R_(f) value: 0.33 (Silica gel; cyclohexane/ethyl acetate=1:1)

(4) N-2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-N-(2,2-dimethoxyethyl)-N'-(2-methoxycarbonyl-1,2,3,4-tetrahydro-6-naphthyl)-urea

The6-amino-2-methoxycarbonyl-1,2,3,4-tetrahydro-naphthalenehydrochloride(Melting point: 260°-261° C.) used as starting material is obtained byrefluxing 2-cyano-6-amino-1,2,3,4-tetrahydronaphthalene insemi-concentrated hydrochloric acid and subsequent esterification withthionylchloride/methanol.

R_(f) value: 0.40 (Silica gel; cyclohexane/ethyl acetate=1:1).

(5) N- 4-(4-quinuclidinyl)phenyl!-N'-(2,2-diethoxyethyl)-N'-trans-4-(methoxycarbonyl)cyclohexyl!-urea

R_(f) value: 0.22 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4).

(6) N-(2,2-diethoxyethyl)-N- trans-4-(methoxycarbonyl)cyclohexyl!-N'-4-(4-methyl-1-trifluoroacetyl-4-piperidinyl)phenyl!-urea

R_(f) value: 0.70 (Silica gel; methylene chloride/ethyl acetate=4:1).

(7) N- 4-(benzyloxy)phenyl!-N'-(2,2-diethoxyethyl)-N'-trans-4-(methoxycarbonyl)cyclohexyl!-urea

R_(f) value: 0.35 (Silica gel; methylene chloride/ethyl acetate=100:5).

EXAMPLE XXI

1-Cyano-3-2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3-(2-hydroxyethyl)-4- 4-2-(methoxycarbonyl)-ethyl!phenyl!-quanidine

7.1 g of cyanimino- 4- 2-(methoxycarbonyl) ethyl!phenyl!-phenoxy-methaneand 7.2 g of N- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-ethanolamine (prepared by reacting 1-tert.butyloxycarbonyl-4-2-(methanesulfonyloxy)ethyl!-piperidine with ethanolamine) are ref luxedin 150 ml of isopropanol for 20 hours. The reaction mixture isevaporated down and the residue is purified by chromatography over asilica gel column with methylene chloride/ethyl acetate (4:6).

Yield: 4.6 g (46% of theory); R_(f) value: 0.26 (Silica gel, methylenechloride/ethyl acetate=4:6).

EXAMPLE XXII

Cyanimino- 4- 2-(methoxycarbonyl)ethyl!phenyl!-phenoxymethane

7.3 g of diphenyl cyanocarbimidate and 5.0 g of methyl3-(4-aminophenyl)propionate are stirred in 100 ml of isopropanol atambient temperature for 20 hours. The solid matter is suction filtered,washed with isopropanol and petroleum ether and dried at 50° C.

Yield: 7.3 g (81% of theory); Melting point: 156°-158° C.; R_(f) value:0.62 (Silica gel, methylene chloride/ethyl acetate=9:1).

EXAMPLE XXIII

4-(2-Hydroxyethyl)-quinuclidine×BH₃

7 g of 70% perchloric acid are added dropwise, with stirring, to 2.65 gof 4-(2-methoxyvinyl)-quinuclidine in 20 ml of toluene. After 1.5 hoursstirring at ambient temperature the mixture is diluted with toluene andmade alkaline with saturated potassium carbonate solution. The organicphase is decanted off and the aqueous phase is stirred 3 times withtert.butyl-methylether. The combined organic phases are evaporated down.The residue is dissolved in 20 ml of water and mixed with 360 mg ofsodium borohydride. After standing overnight the mixture is acidifiedwith citric acid, made alkaline once more and extracted several timeswith tert.butyl-methylether, ethyl acetate and methyl-ethyl-ketone. Thecombined organic phases are dried and evaporated down. The residue isdissolved in 20 ml of tetrahydrofuran and mixed with 15 ml of 1M boranein tetrahydrofuran under nitrogen in a dry ice bath. After standing atambient temperature overnight 1 ml of methanol is added dropwise and themixture is evaporated down. The residue is taken up intert.butyl-methylether, washed with water and saline solution, dried andevaporated down. The residue is purified by chromatography over a silicagel column with cyclohexane/ethyl acetate (1:1).

Yield: 0.80 g (30% of theory); R_(f) value: 0.15 (Silica gel;cyclohexane/ethyl acetate=1:1).

EXAMPLE XXIV

4-(2-Methoxyvinyl)-quinuclidine

To 9.93 g of methoxymethyl-triphenylphosphonium chloride in 45 ml oftetrahydrofuran 17.6 ml of 1.6M n-butyllithium in hexane are addeddropwise, with stirring at ambient temperature. After 10 minutes asolution of 3.4 g of quinuclidine-4-aldehyde in 20 ml of tetrahydrofuranis added dropwise at 0° C. After 3 hours stirring at ambient temperaturethe mixture is evaporated down, the residue is cooled in an ice bath andmixed with 20 ml of 2N citric acid solution and some ice water. It isextracted 3 times with chloroform. The aqueous phase is evaporated downsomewhat, made alkaline and extracted with tert.butylmethylether. Thecombined extracts are dried and evaporated down.

Yield: 2.4 g (58% of theory); R_(f) value: 0.27 and 0.36 (Silica gel;methylene chloride/methanol/conc. aqueous ammonia=80:20:3)

EXAMPLE XXV

4-(4-Iodophenyl)-1-trifluoroacetyl-piperidine

24.6 g of 4-phenyl-1-trifluoroacetyl-piperidine (prepared by reacting4-phenylpiperidine with trifluoroacetic acid anhydride in the presenceof N-ethyl-diisopropylamine), 9.7 g of iodine, 4.5 g of periodicacid-dihydrate, 47.9 ml of glacial acetic acid, 9.6 ml of water and 1.4ml of conc. sulfuric acid are stirred for 6 hours at 70° C. Afterstanding overnight at ambient temperature the mixture is evaporated todryness, mixed with toluene and evaporated down once more. The residueis stirred vigorously with 600 ml of tert.butylmethylether and 300 ml of15% sodium disulphite solution for 5 minutes. It is suction filtered,the organic phase is separated off and extracted twice with sodiumdisulphite solution. The organic phase is separated off, dried andevaporated down. The residue is purified by chromatography over a silicagel column using cyclohexane/ethyl acetate (3:1).

Yield: 18.3 g (50% of theory, contains about 10% starting material);R_(f) value: 0.43 (Silica gel; cyclohexane/ethyl acetate=4:1)

EXAMPLE XXVI

3- 4- 2-(Methoxycarbonyl)ethyl1phenyl!-hydantoin

22.1 g of N- (ethoxycarbonyl)methyl!-N'- 4-2-(methoxycarbonyl)-ethyl!phenyl!-urea in 200 ml of toluene are mixedwith 100 mg of potassium tert.butoxide at boiling temperature and thenrefluxed. After 30 minutes 200 mg of potassium tert.butoxide are addedand the mixture is heated for a further 30 minutes. The reaction mixtureis cooled, mixed with 0.3 ml of glacial acetic acid and evaporated down.The residue is distributed between water and ethyl acetate, the organicphase is separated off, washed with saline solution, dried andevaporated down. The residue is purified by chromatography over a silicagel column with cyclohexane/ethyl acetate (3:7).

Yield: 14.4 g (77% of theory); Melting point: 110°-112° C.; R_(f) value:0.37 (Silica gel; cyclohexane/ethyl acetate=2:8)

The following compound is obtained analogously to Example XXVI:

(1) 1- 4- 2-(methoxycarbonyl)ethyl!phenyl!-hydantoin

Prepared from N- (aminocarbonyl)methyl!-N-(methoxycarbonyl)-4-2-(methoxycarbonyl)ethyl!-aniline in the presence of 1 molar equivalentof potassium tert.butoxide.

Melting point: 228°-233° C.; R_(f) value: 0.42 (Silica gel; methylenechloride/methanol=95:5)

EXAMPLE XXVII

1- 4- 2-(Methoxycarbonyl)ethyl!phenyl!-4,5-dimethyl-3H-imidazol-2-one

2.4 g of N- 4- 2-(methoxycarbonyl)ethyl!phenyl!-urea melting point:152°-154° C. (sintering from 145° C.); prepared from methyl3-(4-aminophenyl)propionate by reacting with potassium cyanate in thepresence of glacial acetic acid! and 2.9 g of acetoin are heated to 180°C. for 1 hour under nitrogen. The reaction mixture is cooled stirredwith ice water and the solid substance is suction filtered. The productis washed with water and diethylether and dried at 100° C.

Yield: 1.6 g (54% of theory); Melting point: 176°-181° C.; R₄ value:0.11 (Silica gel; cyclohexane/ethyl acetate=2:8)

EXAMPLE XXVIII

N- (Aminocarbonyl)methyl!-N-(methoxycarbonyl)-4-2-(methoxycarbonyl)ethyl!-aniline

To 21.8 g of N-(carboxymethyl)-N-(methoxycarbonyl)-4-2-(methoxycarbonyl)ethyl!-aniline R_(f) value: 0.57 (silica gel;toluene/dioxane/ethanol/glacial acetic acid=90:10:10:6), prepared byhydrogenating N-(benzyloxycarbonyl)methyl!-N-(methoxycarbonyl)-4-(2-(methoxycarbonyl)ethyl!-anilinein the presence of. palladium/activated charcoal! in 70 ml of methylenechloride, 7.3 ml of thionyl chloride are rapidly added dropwise and onedrop dimethylformamide is added. The mixture is refluxed for 4 hours,cooled, left to stand overnight and then evaporated down. It is mixedwith toluene and again concentrated by rotary evaporation. The residueis taken up in 200 ml of dioxane and ammonia is passed over the solutionuntil an ammonical reaction is obtained. The reaction mixture isevaporated down, the residue is stirred with ice water and the solidmatter is suction filtered. The product is washed with water andtert.butyl-methylether and dried.

Yield: 16.2 g (75% of theory); R_(f) value: 0.30 (Silica gel;toluene/dioxane/ethanol/glacial acetic acid=90:10:10:6)

EXAMPLE XXIX

N- (Benzyloxycarbonyl)methyl!-N-(methoxycarbonyl)-4-2-(methoxycarbonyl)ethyl!-aniline

To 29.5 g of N- (benzyloxycarbonyl)methyl!-4-2-(methoxycarbonyl)ethyl!-aniline R_(f) value: 0.42 (Silica gel;cyclohexane/ethyl acetate=7:3), prepared by reacting methyl3-(4-aminophenyl)propionate with benzyl bromoacetate in the presence ofN-ethyl-diisopropyl-amine! and 0.3 g of 4-dimethylaminopyridine in 200ml of pyridine, 27 ml of methyl chloroformate are added dropwise whilstcooling with ice. Then the mixture is stirred overnight at ambienttemperature. A further 14 ml of methyl chloroformate are added dropwiseand again the mixture is stirred overnight. The reaction mixture isevaporated down, the residue is distributed between water and ethylacetate and the organic phase is separated off. After washing withcitric acid solution, water and saline solution, the mixture is driedand evaporated down. The residue is purified by chromatography over asilica gel column with cyclohexane/ethyl acetate (75:25).

Yield: 31.0 g (89% of theory); R_(f) value: 0.31 (Silica gel;cyclohexane/ethyl acetate=7:3)

EXAMPLE XXX

1- 4- 2-(Methoxycarbonyl)ethyl!phenyl!-3H-benzimidazol-2-one

To a solution of 1.2 g of 2- 4-2-(methoxycarbonyl)ethyl!-phenyl!amino!-aniline in 5 ml of methylenechloride are added 0.94 g of N,N'-carbonyldiimidazole and the mixture isstirred overnight at ambient temperature. The reaction mixture isdiluted with methylene chloride, washed with citric acid solution andwater, dried and concentrated by rotary evaporation. The residue ispurified by chromatography over a silica gel column with methylenechloride/ethyl acetate (75:25).

Yield: 0.9 g (69% of theory); Melting point: 168°-170° C. R_(f) value:0.31 (Silica gel; cyclohexane/ethyl acetate=1:1)

EXAMPLE XXXI

1- 2-(1-tert.Butyloxycarbonyl-4-piperidinyl)ethyl!imidazolidin-2-one

To 8.9 g of imidazolidin-2-one in 150 ml of dimethylformamide are added10.4 g of potassium tert.-butoxide and the mixture is heated to 70° C.for 30 minutes. To this are added 3.5 g of1-tert.butyloxycarbonyl-4-(2-iodo-ethyl)-piperidine in 5 ml ofdimethylformamide and the mixture is stirred overnight at ambienttemperature. Then 5.3 ml of glacial acetic acid are added dropwise, thereaction mixture is evaporated down and the residue is twice evaporateddown with toluene. The residue is distributed between ethyl acetate andwater, the aqueous phase is extracted four more times with ethyl acetateand the combined organic phases are washed with water, dried andconcentrated by rotary evaporation. The residue is purified bychromatography over a silica gel column with ethyl acetate/methanol(100:3).

Yield: 1.9 g (61% of theory); Melting point: 111°-113° C.; R_(f) value:0.30 (Silica gel; methylene chloride/methanol=100:4)

EXAMPLE XXXII

2-Cyano-6-amino-1,2,3,4-tetrahydronaphthalene

0.92 ml of bromine are added slowly, dropwise, to 4.0 g of sodiumhydroxide in 25 ml water on ice. The mixture is stirred for 10 minutes,then, 3.0 g of finely pulverized2-cyano-6-aminocarbonyl-1,2,3,4-tetrahydro-napthalene (Melting point:180°-182° C., produced by reacting2-cyano-1,2,3,4-tetrahydro-napthalene-6-carbonic acid with thionylchloride followed by treatment with concentrated aqueous ammonia in thepresence of dioxane) are added, and the mixture is removed from thecooling bath. After 4 hours, 2.5 g of sodium disulphite are added, andthe mixture is adjusted to a pH of 1-2, on ice, with hydrochloric acid.The mixture is stirred for 15 minutes, warmed to ambient temperature andfiltered. On ice, the mother liquor is made alkaline with sodiumhydroxide, the precipitate is suction filtered, washed with ice-coldwater and dried.

Yield: 0.87 g (34% of theory), Melting point: 120°-122 ° C.; R_(f)value: 0.50 (Silica gel; cyclohexane/ethyl acetate=1:1)

EXAMPLE XXXIII

1- 4- 2-(Methoxycarbonyl)ethenyl!-2-fluoro-phenyl!-imidazolidin-2-one

19.55 g of 1-(4-bromo-2-fluoro-phenyl)-imidazolidin-2-one, 1.96 g ofpalladium(II)acetate, 2.61 g of tri-o-tolylphosphine, 21.7 ml of methylacrylate, 54.5 ml of triethylamine and 32.6 ml of dimethylformamide arestirred together for 2.5 days at a bath temperature of 100° C. Themixture is cooled, evaporated down and the residue is purified bychromatography over a silica gel column with methylene chloride/methanol(100:1).

Yield: 9.07 g (46% of theory), Melting point: 182°-184° C.; R_(f) value:0.58 (Silica gel; methylene chloride/methanol 20:1)

The following compounds are obtained analogously to Example XXXIII:

(1) 1- 4-2-(methoxycarbonyl)ethenyl!-2-trifluoromethyl-phenyl!-imidazolidin-2-one

Melting point: 145°-150° C.

(2) 1- 4- 2-(methoxycarbonyl)ethenyl!2-methyl-phenyl!-imidazolidin-2-one

Melting point: 149°-151° C.

(3) methyl 3-(4-amino-3-cyano-phenyl)acrylate

The starting material, 4-bromo-2-cyano-aniline-hydrobromide, is obtainedby reacting 2-cyano-aniline with bromine in glacial acetic acid.

R_(f) value: 0.48 (Silica gel; cyclohexane/ethyl acetate=2:1)

The product is converted into methyl3-(4-amino-3-cyano-phenyl)-propionic acid by hydrogenation in ethylacetate in the presence of palladium on activated charcoal.

R_(f) value: 0.55 (Silica gel; cyclohexane/ethyl acetate=2:1)

EXAMPLE XXXIV

1-Benzyl-4-methyl-4-phenyl-piperidine

38.4 ml of 1.6M butyl lithium in hexane are added dropwise to 15.3 g of1-benzyl-4-phenyl-1,2,3,6-tetrahydro-pyridine in 160 ml oftetrahydrofuran at -10° to -15° C. The mixture is stirred for 15minutes, cooled to -50° C. and at this temperature, a solution of 10.7 gof methyl iodide in 140 ml of tetrahydrofuran is added, dropwise. Themixture is warmed to 15° C. within an hour, 80 ml of water are added andthe phases are separated. The organic phase is washed with water andsaturated saline solution, dried and evaporated down. The residue ishydrogenated for 8 hours in 150 ml of ethanol in the presence of 2.0 gof palladium on charcoal (10% palladium) at ambient temperature andunder a hydrogen pressure of 50 psi. The mixture is filtered and thefiltrate is evaporated down. The residue is purified by chromatographyover a silica gel column with methylene chloride/ethanol/conc. aqueousammonia (100:3:0.4).

Yield: 4.1 g (23% of theory); R_(f) value: 0.37 (Silica gel; methylenechloride/ethanol/conc. aqueous ammonia=100:3:0.4)

EXAMPLE XXXXV

1-Amino-4-cyano-bicyclo 2.2.2!octane-hydrochloride

2.6 ml of ethylchloroformate are rapidly added, dropwise, to a solutionof 4.9 g of 1-carboxy-4-cyano-bicyclo 2.2.2!-octane and 3.8 ml oftriethylamine in 130 ml of chloroform at -10° C. After 15 minutes ofstirring, ammonia gas is introduced to the mixture for 10 minutes. Themixture is stirred for 10 minutes at 0° C., warmed to ambienttemperature and after an hour, evaporated to dryness. The residue isstirred with water under heating, cooled, suction filtered, washed withwater and dried. The 1-aminocarbonyl-4-cyano-bicyclo 2.2.2!octane 4.2 g(86% of theory); R_(f) value: 0.78 (Silica gel; methylenechloride/methanol/conc. aqueous ammonia=4:1:0.2)! obtained is suspendedin 100 ml of acetonitrile/water (1:1), combined with 15.0 g ofbis(trifluoroacetoxy)iodobenzene and stirred for 18 hours at ambienttemperature. The reaction mixture is evaporated down to half its volume,shaken twice with ehtyl acetate and the aqueous phase is adjusted to apH of 12 to 13. The aqueous phase is extracted 3 times with ethylacetate and the combined organic phases are washed with saturated salinesolution and dried. The residue is dissolved in ethyl acetate acid and alittle acetone and ethereal hydrochloric acid are added. The mixture iscooled in an ice-bath, suction filtered and the product is washed withethyl acetate.

Yield: 2.5 g (58% of theory); Melting point: >250° C.; R_(f) value: 0.85(Reversed Phase Silica gel; methanol/5% aqueous saline solution=6:4)

EXAMPLE XXXVI

Methyl (trans-4-aminocyclohexyl) oxyacetate-hydrochloride

To a solution of 59.4 g of tert.butyl(trans-4-aminocyclohexyl)oxyacetatein 500 ml of methanol cooled in an ice-bath, hydrochloric acid gas isintroduced for 1 hour and the mixture is stirred overnight at ambienttemperature. The mixture is evaporated to dryness and the residue istriturated with acetone and the solid material is suction filtered anddried.

Yield 34.3 g (59% of theory), Melting point: 157°-160° C.

EXAMPLE XXXVII 3-(2-Hydroxyethyl)-pyrrolidine

a) 1-Benzyloxycarbonyl-2-pyrrolidinone

Prepared by the treatment of 2-pyrrolidinone with potassiumtert.butoxide followed by reaction with benzylchloroformate.

Boiling point: 148°-155° C. (0.2 mbar); R_(f) value: 0.36 (Silica gel;cyclohexane/ethyl acetate=1:1)

b) 1-Benzyloxycarbonyl-3-(tert.butyloxycarbonylmethyl)-2-pyrrolidinone

Prepared by the treatment of 1-benzyloxycarbonyl-2-pyrrolidinone withlithium-bis-(trimethylsilylamide), followed by reaction with tert.butylbromoacetate at -70° C.

R_(f) value: 0.64 (Silica gel; cyclohexane/ethyl acetate=1:1)

c) 3-(tert.Butyloxycarbonylmethyl)-2-pyrrolidinone

Prepared by the catalytic hydrogenation of1-benzyloxy-carbonyl-3-(tert.butyloxycarbonylmethyl)-2-pyrrolidinone inethyl acetate in the presence of palladium/activated charcoal.

R_(f) value: 0.20 (Silica gel; cyclohexane/ethyl acetate=1:1)

d) 3-(2-Hydroxyethyl)-pyrrolidine

Prepared by reacting 3-(tert.butyloxycarbonylmethyl)-2-pyrrolidinonewith lithium aluminium hydride.

R_(f) value: 0.89 (Reversed Phase Silica gel; methanol/15% aqueoussaline solution=6:4)

EXAMPLE XXXVIII 1-Benzyl-4-(2-chloroethyl)-1-azoniabicyclo2.2.2!octanechloride

a) 1-Benzyl-4,4-bis-(ethoxycarbonYlmethyl)-piperidine

Prepared analogously to S. M. McElvain and R. E. Lyle, Jr., J. Am. Chem.Soc. 72, 384 (1950) from 1-benzyl-4-piperidinone.

R_(f) value: 0.48 (Silica gel; methylene chloride/methanol=95:5)

b) 1-Benzyl-4,4-bis-(2-hydroxyethyl)-piperidine

Prepared analogously to M. E. Freed and L. M. Rice, J. HeterocyclicChem. 2, 214 (1965) from1-benzyl-4,4-bis-(ethoxycarbonylmethyl)-piperidine

R_(f) value: 0.18 (Silica gel; methylene chloride/methanol=9:1)

c) 1-Benzyl-4,4-bis-(2-chloroethyl)-piperidine-hydrochloride

Prepared analogously to M. E. Freed and L. M. Rice, J. HeterocyclicChem. 2, 214 (1965) from 1-benzyl-4,4-bis-(2-hydroxyethyl)-piperidine.

Melting point: 168°-170° C.

R_(f) value: 0.45 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

d) 1-Benzyl-4-(2-chloroethyl)-1-azoniabicyclo 2.2.2!octane-chloride

10.5 g of 1-benzyl-4,4-bis-(2-chloroethyl)-piperidine-hydrochloride in50 ml of tert.butyl-methylether are added to 31 ml of 1N sodiumhydroxide solution with vigorous stirring. After stirring for 15minutes, the organic phase is evaporated down. The residue is taken upin 30 ml of acetonitrile and heated at 80° C. for 15 minutes, cooled andevaporated down. The residue is stirred overnight in acetone, the solidmaterial is suction filtered, washed with acetone and ether and dried ina desiccator.

Yield: 7.16 g (77% of theory), Melting point: 199°-201 ° C.; R_(f)value: 0.55 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

EXAMPLE 1

2-(4-Amidinophenyl)-4-4-(1-carboxy-2-propyl)phenyl!-5-methyl-4H-1,2,4-triazol-3-one×0.25 water

0.5 g of 2-(4-amidinophenyl)-4-4-(1-methoxycarbonyl-2-propyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydro-chlorideare stirred in a mixture of 5 ml of semi-concentrated hydrochloric acidand 1 ml of glacial acetic acid at ambient temperature. After 30, 70 and100 minutes, each time a further 1 ml of glacial acetic acid is addedand the mixture is stirred overnight. It is evaporated to dryness, mixedwith 5 ml of water and adjusted to a pH of 6 with 1N sodium hydroxidesolution, with stirring. The precipitate is suction filtered, washedwith a little ice water and dried.

Yield: 0.41 g (92% of theory); R_(f) value: 0.55 (Reversed Phase Silicagel; methanol/10% aqueous saline solution=3:1); Calculated: C 62.57 H5.65 N 18.24; Found: 62.70 5.71 18.00

The following compounds are obtained analogously to Example 1:

(1) 2-(4-amidinophenyl)-4-4-(2-carboxy-1-propyl)phenyl!-5-methyl-4H-1,2,4-triazol-3-one×0.5 water

R_(f) value: 0.55 (Reversed Phase Silica gel; methanol/10% aqueoussaline solution=3:1); Calculated: C 61.85 H 5.71 N 18.03; Found: 61.975.77 18.05

(2) 2-(4-amidinophenyl)-4-4-(2-carboxyethyl)phenyl!-5-phenyl-4H-1,2,4-triazol-3-one×2 water

R_(f) value: 0.47 (Reversed Phase Silica gel; methanol/10% aqueoussaline solution=3:1); Calculated: C 62.47 H 5.46 N 14.88; Found: 62.235.18 15.18

(3) 1-(1-amino-1,2,3,4-tetrahydronaphthalin-6-yl)-3-4-(2-carboxyethyl)phenyl!-imidazolidin-2-one-hydrochloride

Melting point: 236°-238° C.; R_(f) value: 0.39 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 63.53 H6.30 N 10.10 ° C.l 8.52; Found: 63.81 6.50 10.00 8.21

(4) 4- 4-(2-carboxyethyl)phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-toluenesulphonate×water

The starting material was present as toluenesulphonate.

R_(f) value: 0.59 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution 6:4); Calculated,: C 56.92 H 6.61 N 10.21 S 5.84; Found: 56.826.74 9.95 5.88

(5) 1-(4-amidinophenyl)-3-trans-4-(2-carboxyethyl)cyclohexyl!-imidazolidin-2,4-dione

R_(f) value: 0.45 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(6) 1- 4-(2-carboxyethyl)phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride×water

Melting point: 216°-225° C.; R_(f) value: 0.54 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 57.06 H7.56 N 10.51 Cl 8.86; Found: 57.27 7.55 10.61 9.14

(7) 1- 4-(2-carboxy-1-pentyl)phenyl!-3-2-(4-piperidinyl)-ethyl!-imidazolidin-2-one-hydrochloride

(8) 4-4-(2-carboxy-1-pentyl)phenyl!-5-methyl-2-(2-(4-piperidinyl)ethyl)-4H-1,2,4-triazol-3-one-hydrochlorideR_(f) value: 0.44 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(9) 4- 4-(2-carboxy-3-methyl-1-butyl)phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydro-chloride

(10) 4- 4-(2-carboxy-1-butyl)phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(11) 4- 4-(2-carboxy-1-propyl)phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(12) 2-(4-amidinophenyl)-4-4-(2-carboxy-1-pentyl)phenyl!-5-methyl-4H-1,2,4-triazol-3-one

(13) 4-(4-amidinophenyl)-2-trans-4-(2-carboxyethyl)cyclohexyl!-4H-1,2,4-triazol-3-one

(14) l- 4-(2-carboxyethyl)phenyl!-3-2-(4-piperidinyl)-ethyl!-3,4,5,6-tetrahydro-1H-pyrimidin-2-one-hydro-chloride

R_(f) value: 0.60 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Mass spectrum: (M+H)⁺ =360

(15) 1-(4-amidinophenyl)-3- trans-4-(carboxymethyl)oxy!-cyclohexyl!-imidazolidin-2-one

(16) 2- 4-(aminomethyl)phenyl!-4-4-(2-carboxy-1-propyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

R_(f) value: 0.69 (Reversed Phase Silica gel; methanol/10% aqueoussaline solution=3:1)

(17) 4- 4-(2-carboxyethyl)phenyl!-5-methyl-2-(1-piperazinyl)carbonylmethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(18) 4- 4-(2-carboxyethyl)phenyl!-5-methyl-2-2-(1-aza-4-cycloheptyl)ethyl!-4H-1,2,4-triazol-3-one-hydro-chloride

(19) 4- 4-(2-carboxyethyl)phenyl!-5-methyl-2-2-(1,4-diaza-1-cycloheptyl)ethyl!-4H-1,2,4-triazol-3-one-dihydrochloride

(20) l-4-(4-carboxybutyl)phenyl!-3-(4-piperidinyl)imidazolidin-2-one-hydrochloride

Melting point: 223°-225° C.; R_(f) value: 0.46 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4)

(21) 1-(4-amidinophenyl)-3- 4- 2-(n-butylsulfonylamino)-2-carboxy-ethyl!phenyl!-imidazolidin-2-one-hydrochloride R_(f) value: 0.43(Reversed Phase Silica gel; methanol/5% aqueous saline solution=6:4)

(22) 4- 4-(2-(n-butylsulfonylamino)-2-carboxy-ethyl)phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(23) 1-(4-amidinophenyl)-3- 4-2-carboxy-2-(n-hexanoyl-amino)-ethyl!phenyl!-imidazolidin-2-one-hydrochloride

(24) 1-(4-amidinophenyl)-3- 4-2-carboxy-2-(3-phenyl-propionylamino)-ethyl!phenyl!-imidazolidin-2-one-hydrochloride

(25) 1-(4-amidinophenyl)-3- 4-2-(benzylsulfonylamino)-2-carboxy-ethyl!phenyl!-imidazolidin-2-one-hydrochloride

(26) 4- 4- 2-carboxy-2-(methanesulfonylamino)-ethyl!phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(27) 4- 4- 2-(acetylamino)-2-carboxy-ethyl!phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(28) 4- 4-(2-carboxy-1-octyl)phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(29) 4- 4-(2-carboxyethyl)phenyl!-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one×1.05 HCl×0.25 H₂ O

Melting point: 252°-255° C.; R_(f) value: 0.65 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 55.84 H6.65 N 14.47 ° C.l 9.61; Found: 55.73 6.73 14.49 9.60

(30) 2- 4-(2-carboxyethyl)phenyl!-5-2-(4-piperidinyl)ethyl!-3,4-dihydro-2H,5H-1,2,5-thiadiazole-l,1-dioxideR_(f) value: 0.71 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(31) 1- 4-(2-carboxyethyl)phenyl!-3-(1-piperazinyl)carbonylmethyl!-imidazolidin-2-one-hydrochloride

R_(f) value: 0.58 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4);

Mass spectrum: M⁺ =360

(32) 1- 4- 2-(n-butylsulfonylamino)-2-carboxy-ethyl!phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride

R_(f) value: 0.51 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(33) 4- 4-(2-carboxyethyl)phenyl!-2-2-(1-piperazinyl)ethyl!-4H-1,2,4-triazol-3-one×2.1 HCl×0.15 H₂ O

R_(f) value: 0.69 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 48.08 H 6.03 N 16.49 ° C.l 17.53; Found:48.28 6.11 16.45 17.40 Mass spectrum: M⁺ =345

(34) 1- 4-(2-carboxyethyl)phenyl!-3-2-(4-piperidinyl)ethyl!-3H-benzimidazol-2-one×1.1 HCl×0.4 H₂ O

R_(f) value: 0.38 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 62.67 H 6.61 N 9.53 Cl 8.85; Found: 63.066.58 9.48 8.51

(35) 1- 4-(aminomethyl)-bicyclo 2.2.2!octan-1-yl!-3-4-(2-carboxyethyl)phenyl!-imidazolidin-2-one-hydrochloride

Melting point: 334°-336° C.; R_(f) value: 0.43 (Reversed Phase Silicagel; methanol/5% aqueous saline=6:4)

(36) 1-4-(trans-4-carboxycyclohexyl)phenyl!-3-(4-piperidinyl)-imidazolidin-2-one-hydrochloride

(37) 2- 4-(2-carboxyethyl)phenyl!-5-methyl-4-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(38) 1- 2-(1-aza-4-cycloheptyl)ethyl!-3-4-(2-carboxyethyl)-phenyl!-imidazolidin-2-one-hydrochloride

Melting point: 205°-207° C.; R_(f) value: 0.52 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 60.67 H7.64 N 10.61 Cl 8.96; Found: 60.37 7.85 10.73 9.05

(39) 1- trans-4-(2-carboxyethyl)cyclohexyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride

R_(f) value: 0.55 (Reversed Phase Silica gel; nethanol/5% aqueous salinesolution=6:4); Calculated: C 58.82 H 8.83 N 10.83 Cl 9.14; Found: 58.529.04 10.65 9.02

(40) 1- 4-(2-carboxyethyl)phenyl!-3-2-(2,2,6,6-tetramethyl-4-piperidinyl)ethyl!-imidazolidin-2-one-hydro-chloride

Melting point: >250° C.; R_(f) value: 0.44 (Reversed Phase Silica gel;methanol/5% aqueous saline solution=6:4)

(41) 1- 4-(2-carboxyethyl)phenyl!-3-2-(4-piperidinyl)ethyl!-hydantoin-hydrochloride×0.6 H₂ O

Melting point: 226°-230° C. (sintering from 220° C.) R_(f) value: 0.56(Reversed Phase Silica gel; methanol/5% aqueous saline solution=6:4);Calculated: C 56.11 H 6.74 N 10.33 Cl 8.71; Found: 55.72 6.71 10.32 9.11

(42) 3- 4-(2-carboxyethyl)phenyl!-1-2-(4-piperidinyl)ethyl!-hydantoin-hydrochloride

Melting point: 186°-189° C. R_(f) value: 0.66 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 57.64 H6.62 N 10.61 Cl 8.96; Found: 57.52 6.81 10.39 8.86

(43) 1- 4-(2-carboxyethyl)phenyl!-3-2-(4-piperidinyl)ethyl!-cis-4,5-dimethyl-imidazolidin-2-one-hydro-chloride

Melting point: 157°-163° C. R_(f) value: 0.53 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4)

(44)1-(2-aminomethyl-1,2,3,4-tetrahydro-6-naphthyl)-3-(trans-4-carboxycyclohexyl)-imidazolidin-2-one-hydrochloride

R_(f) value: 0.55 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 61.83 H 7.41 N 10.30 Cl 8.69; Found: 61.867.44 10.30 8.80

(45) 1-(trans-4-carboxycyclohexyl)-3-4-(3-oxo-4-quinuclidinyl)phenyl!-imidazolidin-2-one-hydrochloride

(46) 1-(5-aminopentyl)-3-4-(2-carboxyethyl)phenyl!-imidazolidin-2-one-hydrochloride×0.2 H₂ O

Calculated: C 56.80 H 7.40 N 11.69 Cl 9.86; Found: 56.62 7.42 11.98 9.46

(47) 1- 3-(cis-1-amino-2-cyclopentyl)propyl!-3-4-(2-carboxyethyl)phenyl!-imidazolidin-2-one-hydrochloride

(48) 1- 2- (cis-1-amino-2-cyclopentyl)oxy!ethyl!-3-4-(2-carboxyethyl)phenyl!-imidazolidin-2-one-hydrochloride

(49) 1-(2-carboxy-1,2,3,4-tetrahydro-6-naphthyl)-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride×1 H₂ O

Melting point: 274°-278° C.; Calculated: C 59.21 H 7.57 N 9.86 Cl 8.32;Found: 59.23 7.49 9.87 8.27; Mass spectrum: M⁺ =371

(50) 1-(trans-4-carboxycyclohexyl)-3-4-(4-quinuclidinyl)-phenyl!-imidazolidin-2-one-hydrochloride×1.2 H₂ O

R_(f) value: 0.55 (Reversed Phase Silica gel; methanol/5% aqueous saline6:4); Calculated: C 60.63 H 7.61 N 9.22 Cl 7.78; Found: 60.47 7.60 9.367.95; Mass spectrum: M⁺ =397

(51) 1-(trans-4-carboxycyclohexyl)-3- 4-(2-aminoethyl)oxy!phenyl!imidazolidin-2-one-hydrochloride

R_(f) value: 0.58 (Reversed Phase Silica gel; methanol/5% aqueoussaline=6:4)

EXAMPLE 2

2-(4-Amidinophenyl)-4-4-(1-methoxycarbonyl-2-propyl)phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

3.2 g of 2-(4-cyanophenyl)-4-4-(1-ethoxycarbonyl-2-propyl)phenyl!-5-methyl-4H-1,2,4-triazol-3-one,suspended in 75 ml of dry methanol, are added to 120 ml of dry methanolsaturated with hydrochloric acid gas at 0° C. The mixture is saturatedwith hydrochloric gas at 0° C., some petroleum ether is added and themixture is stirred overnight at ambient temperature. The reactionmixture is evaporated down, 50 ml of dry methanol are added and themixture is evaporated down once more. The residue is dissolved in 120 mlof methanol, methanolic ammonia is added to give a pH of 8-9, 2.28 g ofammonium acetate are added and the mixture is refluxed for 2 hours.After concentration by evaporation the residue is purified bychromatography over a silica gel column with methylene chloride/methanol(4:1). The product is dissolved in methanol/methylene chloride andcombined with 5 ml of methanolic hydrochloric acid with stirring. Thesolution is evaporated almost to dryness, some more toluene is added andit is again evaporated to dryness.

Yield: 2.01 g (57% of theory) R_(f) value: 0.40 (Reversed Phase Silicagel; methanol/10% aqueous saline solution=3:1) The following compoundsare obtained analogously to Example 2:

(1) 2-(4-amidinophenyl)-4-4-(2-methoxycarbonyl-1-propyl)phenyl!-5-methyl-4H-1,2,4-triazol-3-one×1.1hydrogen chloride

R_(f) value: 0.40 (Reversed Phase Silica gel; methanol/10% aqueoussaline solution=3:1); Calculated: C 58.18 H 5.37 N 16.15 Cl 9.00; Found:57.90 5.65 16.24 9.14

(2) 1-(4-amidinophenyl)-3- trans-4-2-(methoxycarbonyl)ethyl!cyclohexyl!-3H-imidazol-2-one-hydrochloride

R_(f) value: 0.59 (Reversed Phase Silica gel; methanol/10% aqueoussaline solution=3:1)

(3) 1-(4-amidinophenyl)-3- cis-4-2-(methoxycarbonyl)ethyl!-cyclohexyl!-3H-imidazol-2-one-hydrochloride

R_(f) value: 0.46 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(4) 2-(4-amidinophenyl)-4- 4-2-(methoxycarbonyl)ethyl!-phenyl!-5-phenyl-4H-1,2,4-triazol-3-one-hydrochloride

R_(f) value: 0.37 (Reversed Phase Silica gel; methanol/10% aqueoussaline solution=3:1)

(5) 1-(4-amidinophenyl)-3- 4-2-(5-tetrazolyl)ethyl!phenyl!-imidazolidin-2-one

R_(f) value: 0.50 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(6) 2-(4-amidinophenyl)-4- trans-4-2-(methoxycarbonyl)ethyl!cyclohexyl!-4H-1,2,4-triazol-3-one-hydrochloride×H₂O

Melting point: 247° C. (decomp.); R_(f) value: 0.35 (Reversed PhaseSilica gel; methanol/5% aqueous saline solution=6:4); Calculated: C53.58 H 6.62 N 16.44 Cl 8.32; Found: 53.80 6.81 16.44 8.17

(7) 1-(4-amidinophenyl)-3- trans-4-2-(methoxycarbonyl)ethyl!cyclohexyl!-imidazolidin-2,4-dione-hydrochloride

R_(f) value: 0.32 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(8) 2-(4-amidinophenyl)-4- 4-2-(methoxycarbonyl)-1-pentyl!-phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

(9) 4-(4-amidinophenyl)-2- trans-4-2-(methoxycarbonyl)ethyl!cyclohexyl!-4H-1,2,4-triazol-3-one-hydrochloride

(10) 1-(4-amidinophenyl)-3- trans-4-(methoxycarbonylmethyl)-oxy!cyclohexyl!-imidazolidin-2-one-hydrochloride

(11) 1-(4-amidinophenyl)-3- 4-2-(n-butylsulfonylamino)-2-(methoxycarbonyl)-ethyl!phenyl!-imidazolidin-2-one-acetateThe product is isolated in the form of the acetate.

Melting point: 220° C. (decomp.); R_(f) value: 0.34 (Reversed PhaseSilica gel; methanol/5% aqueous saline solution=6:4); Calculated: C55.60 H 6.28 N 12.47 S 5.71; Found: 55.64 6.26 12.31 5.61

(12) 1-(4-amidinophenyl)-3- 4-2-(n-hexanoylamino)-2-(methoxycarbonyl)-ethyl!phenyl!-imidazolidin-2-one-hydrochloride

(13) 1-(4-amidinophenyl)-3- 4- 2-(methoxycarbonyl)-2-(3-phenylpropionylamino)-ethyl!phenyl!-imidazolidin-2-one-hydrochloride

(14) 1-(4-amidinophenyl)-3- 4-2-(benzylsulfonylamino)-2-(methoxycarbonyl)-ethyl!phenyl!-imidazolidin-2-one-hydrochloride

(15) 1-(4-amidinophenyl)-3- 4-2-(methoxycarbonyl)ethyl!phenyl!-imidazolidin-2-one-hydrochloride

R_(f) value: 0.45 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=3:2); Calculated: C 59.63 H 5.75 N 13.91 Cl 8.80; Found: 59.595.85 13.70 8.55

(16) 2-(4-amidinophenyl)-4- 4-2-(methoxycarbonyl)ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-acetate

The product is isolated in the form of the acetate.

R_(f) value: 0.32 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=3:2); Calculated: C 59.59 H 5.69 N 15.79; Found: 59.79 5.7216.01

(17) 2-(4-amidinophenyl)-4- 4-2-(methoxycarbonyl)ethyl!phenyl!-5-trifluoromethyl-4H-1,2,4-triazol-3-one-hydrochloride

R_(f) value: 0.37 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=3:2)

EXAMPLE 3

2-(4-Cyanophenyl)-4-4-(1-ethoxycarbonyl-2-propyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one

6.5 g of 1-acetyl-2-(4-cyanophenyl)-4-4-(1-ethoxycarbonyl-2-propyl)phenyl!-semicarbazide are heated for 1.5hours in vacuo in an oil bath pre-heated to 200° C. After cooling, thereaction mixture is purified by chromatography over a silica gel columnusing methylene chloride/ethyl acetate/cyclohexane (20:1:1).

Yield: 3.2g (51% of theory);

Melting point: 134°-138° C.; R_(f) value: 0.51 (Silica gel; methylenechloride/ethyl acetate/cyclohexane=20:1:1);

The following compounds are obtained analogously to Example 3:

(1) 2-(4-cyanophenyl)-4-4-(2-ethoxycarbonyl-1-propyl)phenyl!-5-methyl-4H-1,2,4-triazol-3-one

Melting point: 124°-128° C.; R_(f) value: 0.77 (Silica gel; methylenechloride/ethyl acetate=20:1)

(2) 2-(4-cyanophenyl)-4- cis-4-2-(methoxycarbonyl)ethyl!-cyclohexyl!-5-methyl-4H-1,2,4-triazol-3-one

Melting point: 92°-96° C.; R_(f) value: 0.60 (Silica gel; methylenechloride/ethyl acetate=9:1)

(3) 2-(4-cyanophenyl)-4- trans-4-2-(methoxycarbonyl)ethyl!-cyclohexyl!-5-methyl-4H-1,2,4-triazol-3-one

Melting point: 166°-167° C.; R_(f) value: 0.55 (Silica gel; methylenechloride/ethyl acetate=9:1)

(4) 2-(4-cyanophenyl)-4- 3-2-(methoxycarbonyl)ethyl!-phenyl!-5-methyl-4H-1,2,4-triazol-3-one

Melting point: 134°-137° C.; R_(f) value: 0.67 (Silica gel; methylenechloride/ethyl acetate=9:1)

(5) 2-(4-cyanophenyl)-4- 4-2-(methoxycarbonyl)ethyl!-phenyl!-5-phenyl-4H-1,2,4-triazol-3-one

Melting point: 190°-194° C.; R_(f) value: 0.80 (Silica gel; methylenechloride/ethyl acetate=20:1); Calculated: C 70.74 H 4.75 N 13.20; Found:70.61 4.81 13.41

(6) 2-(4-cyanophenyl)-4- trans-4-2-(methoxycarbonyl)ethyl!-cyclohexyl!-4H-1,2,4-triazol-3-one

Melting point: 152°-153° C.

(7) 2-(4-cyanophenyl)-4- 4-2-(methoxycarbonyl)-1-pentyl!-phenyl!-5-methyl-4H-1,2,4-triazol-3-one

(8) 2-(4-cyanophenyl)-4- 4-2-(methoxycarbonyl)ethyl!-phenyl!-5-methyl-4H-1,2,4-triazol-3-one

Melting point: 162°-165° C.

(9) 2-(4-cyanophenyl)-4- 4-2-(methoxycarbonyl)ethyl!-phenyl!-5-trifluoromethyl-4H-1,2,4-triazol-3-oneCarried out in boiling trifluoroacetic acid.

R_(f) value: 0.46 (Silica gel; cyclohexane/ethyl acetate=2:1)

EXAMPLE 4

2-(4-Amidinophenyl)-4-cis-4-(2-carboxyethyl)cyclo-hexyl!-5-methyl-4H-1,2,4-triazol-3-one

To a solution of 400 mg of 2-(4-amidinophenyl)-4- cis-4-2-(methoxycarbonyl)ethyl!cyclohexyl!-5-methyl-4H-1,2,4-triazol-3-one×1.2hydrogen chloride×1 water in 4 ml of methanol are added 0.71 ml of 4Nsodium hydroxide solution and the mixture is stirred for 4 hours atambient temperature. Then 178 mg of ammonium chloride are added and themixture is stirred for 1 hour. The precipitate is suction filtered,washed with a little cold methanol and dried at 50° C. in vacuo.

Yield: 230 mg (65% of theory); R_(f) value: 0.50 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 61.44 H6.78 N 18.85; Found: 61.21 6.87 18.76

The following compounds are obtained analogously to Example 4:

(1) 2-(4-amidinophenyl)-4-trans-4-(2-carboxyethyl)cyclohexyl!-5-methyl-4H-1, 2, 4-triazol-3-oneR_(f) value: 0.50 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 61.44 H 6.78 N 18.55; Found: 61.38 6.9318.66

(2) 1- (4-amidinophenyl)-3-trans-4-(2-carboxyethyl)cyclohexyl!-imidazolidin-2-one×0.4 H₂ O

R_(f) value: 0.64 (Reversed Phase Silica gel; methanol/10% aqueoussaline solution=3:1); Calculated: C 62.41 H 7.39 N 15.32; Found: 62.507.37 15.00

(3) 1-(4-amidinophenyl)-3-cis-4-(2-carboxyethyl)cyclo-hexyl!-imidazolidin-2-one×0.25 water

R_(f) value: 0.64 (Reversed Phase Silica gel; methanol/10% aqueoussaline solution=3:1); Calculated: C 62.88 H 7.36 N 15.44; Found: 63.007.32 15.19

(4) 2-(4-amidinophenyl)-4- trans-4-(2-carboxyethyl)-cyclohexyl!-4H-1,2,4-triazol-3-one

R_(f) value: 0.44 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(5) 1- 4-(aminomethyl)cyclohexyl!-3-4-(2-carboxyethyl)phenyl!-imidazolidin-2-one

R_(f) value: 0.55 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(6) 1- 4-2-(n-butylsulfonylamino)-2-carboxy-ethyl!phenyl!-3-(4-cyanophenyl)-imidazolidin-2-oneWorked up with hydrochloric acid.

R_(f) value: 0.36 (Silica gel; toluene/dioxane/ethanol/glacial aceticacid=90:10:10:6); Calculated: C 58.71 H 5.57 N 11.91; Found: 58.73 5.6911.82

(7) 2- 4-(benzyloxycarbonylamidino)phenyl!-4-4-(2-carboxyethyl)phenyl!-5-methyl-4H-1,2,4-triazol-3-one

(8) 2-(4-amidinophenyl)-4-4-(2-carboxyethyl)phenyl!-5-methyl-4H-1,2,4-triazol-3-one

R_(f) value: 0.61 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=3:2); Calculated: C 62.46 H 5.24 N 19.17; Cound: 62.21 5.3319.39

(9) 2-(4-amidinophenyl)-4-4-(2-carboxyethyl)phenyl!-5-trifluoromethyl-4H-1 ,2,4-triazol-3-one

R_(f) value: 0.52 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 54.42 H 3.85 N 16.70; Found: 54.29 3.8617.06

(10) 1- 4-(2-carboxyethyl)phenyl!-2-cyanimino-3-2-(4-piperidinyl)ethyl!-imidazolidine×0.95 HCl×0.3 H₂ O

R_(f) value: 0.44 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 58.52 H 7.24 N 17.06 Cl 8.21; Found: 58.847.05 16.89 8.05

(11) 1- 4-(2-carboxyethyl)phenyl!-3-2-(4-piperidinyl)ethyl!-4,5-dimethyl-3H-imidazol-2-one-hydrochloride

R_(f) value: 0.43 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(12) 1- (4-carboxy-1-piperidinyl)carbonylmethyl!-3-2-(4-piperidinyl)ethyl-imidazolidin-2-one

R_(f) value: 0.71 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Mass spectrum: M⁺ =366

(13) 1- 4-(2-carboxyethenyl)-2-fluoro-phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one×1.1 HCl×1 H₂ O

Melting point: 253°-255° C. (decomp.); Calculated: C 54.39 H 6.51 N10.02 Cl 9.29; Found: 54.15 6.43 10.03 9.02

(14) 1-(trans-4-carboxycyclohexyl)-3-4-(1-benzyloxy-carbonyl-4-piperidinyl)phenyl!-imidazolidin-2-one

Melting point: 194°-195° C. R_(f) value: 0.54 (Silica gel; methylenechloride/methanol=9:1)

(15) 1-(2-carboxy-6-naphthyl)-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one.times.0.9 HCl×1 H₂ O

R_(f) value: 0.36 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 60.25 H 6.72 N 10.05 Cl 7.62; Found: 60.156.69 10.11 7.77; Mass spectrum: M⁺ =367

EXAMPLE 5

2-(4-Amidinophenyl)-4- cis-4-2-(methoxycarbonyl)ethyl!-cyclohexyl!-5-methyl-4H-1,2,4-triazol-3-one×1.2hydrogen chloride×1 water

0.9 g of 2-(4-cyanophenyl)-4- cis-4-2-(methoxycarbonyl)ethyl!-cyclohexyl!-5-methyl-4H-1,2,4-triazol-3-one in10 ml of dry methanol are added to 30 ml of dry methanol which has beensaturated with hydrochloric acid gas. The mixture is saturated withhydrochloric acid gas at 0° C. and left to stand overnight at ambienttemperature. It is evaporated to dryness, mixed with dry methanol andevaporated down once more. The residue is taken up in 20 ml of methanoland mixed with 10 ml of concentrated aqueous ammonia and stirredovernight at ambient temperature. It is evaporated to dryness and theresidue is purified by chromatography over a silica gel column usingmethylene chloride/methanol (6:1).

Yield: 600 mg (60% of theory); R_(f) value: 0.37 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 53.71 H6.80 N 15.65 Cl 9.51; Found: 53.74 6.87 15.78 9.01

The following compounds are obtained analogously to Example 5:

(1) 2-(4-amidinophenyl)-4- trans-4-2-(methoxycarbonyl)ethyl!cyclohexyl!-5-methyl-4H-1,2,4-triazol-3-one×1.1hydrogen chloride×0.3 water

R_(f) value: 0.37 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 55.12 H 6.63 N 16.07 Cl 8.95; Found: 55.336.74 15.97 8.88

(2) 2-(4-amidinophenyl)-4-3-(2-carboxyethyl)phenyl!-5-methyl-4H-1,2,4-triazol-3-one (amidino acidobtained directly)

R_(f) value: 0.62 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

EXAMPLE 6

2-(4-Amidinophenyl)-4- 4-2-(ethoxycarbonyl)ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

750 mg of 2-(4-amidinophenyl)-4-4-(2-carboxyethyl)-phenyl!-5-methyl-4H-1,2,4-triazol-3-one are stirredfor 3 hours in ethanolic hydrochloric acid. The reaction mixture isevaporated down, mixed with toluene and evaporated down once more. Thisprocedure is repeated several times, then the residue is stirred withacetone, the product is suction filtered and washed with acetone.

Yield: 770 mg (87% of theory);

Melting point: 279°-283° C. (decomp.); R_(f) value: 0.39 (Reversed PhaseSilica gel; methanol/5% aqueous saline solution=6:4)

The following compounds are obtained analogously to Example 6:

(1) 2-(4-amidinophenyl)-4- 4- 2-(3-pentyl)oxycarbonyl!-ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydro-chloride

R_(f) value: 0.27 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(2) 2-(4-amidinophenyl)-4- 4-2-(neopentyloxycarbonyl)-ethyl!-phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydro-chloride

Melting point: 295°-297° C. (decomp.); R_(f) value: 0.25 (Reversed PhaseSilica gel; methanol/5% aqueous saline solution=6:4)

(3) 2-(4-amidinophenyl)-4- 4-2-(isopropyloxycarbonyl)-ethyl!-phenyl!-5-trifluoromethyl-4H-1,2,4-triazol-3-one-hydrochloride

Melting point: 319°-320° C.; R_(f) value: 0.30 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4)

(4) 2-(4-amidinophenyl)-4- trans-4-2-(isopropyloxycarbonyl)-ethyl!cyclohexyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

R_(f) value: 0.29 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(5) 2-(4-amidinophenyl)-4- cis-4-2-(isopropyloxycarbonyl)-ethyl!cyclohexyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

R_(f) value: 0.29 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(6) 1-(4-amidinophenyl)-3- trans-4-2-(isopropyloxycarbonyl)-ethyl!cyclohexyl!-imidazolidin-2-one-hydro-chloride

R_(f) value: 0.52 (Reversed Phase Silica gel; methanol/10% aqueoussaline solution=3:1)

(7) 1-(4-amidinophenyl)-3- trans-4-2-(ethyloxycarbonyl)-ethyl!cyclohexyl!-imidazolidin-2-one-hydrochloride×0.5water

R_(f) value: 0.55 (Reversed Phase Silica gel; methanol/10% aqueoussaline solution=3:1); Calculated: C 58.39 .H 7.47 N 12.97; Found: 58.587.41 12.94

(8) 1-(4-amidinophenyl)-3- cis-4-2-(isopropyloxycarbonyl)-ethyl!cyclohexyl!-imidazolidin-2-one×1.05hydrogen chloride×0.2 water

R_(f) value: 0.52 (Reversed Phase Silica gel; methanol/10% aqueoussaline solution=3:1); Calculated: C 59.72 H 7.62 N 12.66 Cl 8.41; Found:59.81 7.67 12.83 8.59

(9) 1-(4-amidinophenyl)-3- cis-4-2-(ethoxycarbonyl)ethyl!-cyclohexyl!-imidazolidin-2-one×1.1 hydrogenchloride×0.5 water

R_(f) value: 0.55 (Reversed Phase Silica gel; methanol/10% aqueoussaline solution=3:1); Calculated: C 58.14 H 7.45 N 12.91 Cl 8.99; Found:58.37 7.39 13.08 9.03

(10) 4- 4- 2-(methoxycarbonyl)ethyl!phenyl!-5-methyl-2-2-(1-methyl-4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(11) 1- 4- 2-(methoxycarbonyl)ethyl!cyclohexyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride

(12) 1- trans-4-(methoxycarbonyl)cyclohexyl!-3-4-(4-piperidinyl)phenyl!-imidazolidin-2-one-hydrochloride Using thionylchloride instead of hydrochloric acid gas.

R_(f) value: 0.38 (Reversed Phase Silica gel; methanol/10% aqueoussaline solution=6:4); Mass spectrum: M⁺ =385

(13) 1- 4-(methoxycarbonyl)butyl)-3-4-(4-piperidinyl)phenyl!-imidazolidin-2-one-hydrochloride

(14) 2-(4-amidinophenyl)-4- 4-2-(cyclohexyloxycarbonyl)-ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

R_(f) value: 0.16 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 62.04 H 6.25 N 14.47 Cl 7.33; Found: 61.876.24 14.50 7.60

(15) 2-(4-amidinophenyl)-4- 4-2-(cyclohexylmethyloxycarbonyl)ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

Melting point: 273°-275° C. (decomp.) R_(f) value: 0.10 (Reversed PhaseSilica gel; methanol/5% aqueous saline solution=6:4); Calculated: C62.70 H 6.48 N 14.06 Cl 7.12; Found: 62.43 6.61 14.00 7.27

(16) 2-(4-amidinophenyl)-4- 4-2-(cyclopentyloxycarbonyl)-ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

R_(f) value: 0.22 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 61.34 H 6.01 N 14.90 Cl 7.54; Found: 61.136.03 14.79 7.84

(17) 2-(4-amidinophenyl)-4- 4-2-(cycloheptyloxycarbonyl)-ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

(18) 2-(4-amidinophenyl)-4- 4-2-(cyclooctyloxycarbonyl)-ethyl!phenyl!-5-methyl-4H-1,2,4-triazole-3-one-hydrochloride

(19) 2-(4-amidinophenyl)-4- 4- 2-(2-cyclohexylethyl)oxycarbonyl!ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

(20) 2-(4-amidinophenyl)-4-4-(2-((cyclopentylmethyl)oxycarbonyl!ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

(21) 2-(4-amidinophenyl)-4- 4- 2-(4-methylcyclohexyl)oxycarbonyl!ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

(22) 2-(4-amidinophenyl)-4- 4- 2-(3,5-dimethylcyclohexyl)oxycarbonyl!ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

(23) 2-(4-amidinophenyl)-4- 4- 2-(4-ethylcyclohexyl)oxycarbonyl!ethyl)phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

(24) 2-(4-amidinophenyl)-4- 4-2-(menthyloxycarbonyl)ethyl!-phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

(25) 2-(4-amidinophenyl)-4- 4- 2-(4-methoxycyclohexyl)oxycarbonyl!ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

(26) 2-(4-amidinophenyl)-4- 4- 2-(2-norbornyl)oxycarbonyl!-ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

(27) 2-(4-amidinophenyl)-4- 4- 2-(3-pinanyl)oxycarbonyl!-ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

(28) 2-(4-amidinophenyl)-4- 4-2-(fenchyloxycarbonyl)ethyl!-phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

(29) 2-(4-amidinophenyl)-4- 4-(2-indanyl)oxycarbonyl)ethyl!-phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

(30) 2-(4-amidinophenyl)-4- 4-2-(isopropyloxycarbonyl)-1-propyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

Melting point: 260°-262° C.; R_(f) value: 0.36 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4)

(31) 2-(4-amidinophenyl)-4- 4-2-(isopropyloxycarbonyl)ethyl!phenyl!-5-phenyl-4H-1,2,4-triazol-3-one-hydrochloride

Melting point: 295°-297° C.; R_(f) value: 0.24 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4)

(32) 1- 4- 2-(cyclohexyloxycarbonyl)ethyl!phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride×H₂ O

Melting point: 185°-188° C.; R_(f) value: 0.24 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 62.29 H8.36 N 8.72 Cl 7.35; Found: 62.34 8.38 8.74 8.04

(33) 1- 2-(4-piperidinyl)ethyl!-3- 4-2-(isopropyloxycarbonyl)ethyl!phenyl!-imidazolidin-2-one-hydrochloride

Melting point: 185°-188° C.; R_(f) value: 0.32 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 62.32 H8.08 N 9.91 Cl 8.36; Found: 62.10 8.04 9.96 8.20

(34) 1- 4-2-(ethoxycarbonyl)ethyl!phenyl!-3-(2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochlorideUsing thionyl chloride instead of hydrochloric acid gas.

Melting point: 177°-180° C.; R_(f) value: 0.33 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 61.53 H7.87 N 10.25 Cl 8.65; Found: 61.30 7.92 10.28 8.83

(35) 1- trans-4- 2-(ethoxycarbonyl)ethyl!cyclohexyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride

Using thionyl chloride instead of hydrochloric acid gas.

Melting point: 188°-196° C.; R_(f) value: 0.34 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 60.63 H9.21 N 10.10 Cl 8.52; Found: 60.32 9.17 9.99 8.79

(36) 1- trans-4-2-(isopropyloxycarbonyl)ethyl!cyclohexyl!-3-(2-(4-piperidinyl)ethyl!-imidazolidin-2-one×1.05HCl

Using thionyl chloride instead of hydrochloric acid gas.

Melting point: 194°-199° C.; R_(f) value: 0.26 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 61.15 H9.39 N 9.73 Cl 8.67; Found: 61.00 9.33 9.77 8.75

(37) 1- 2-(4-quinuclidinyl)ethyl!-3- 4-2-(ethoxycarbonyl)-ethyl!phenyl!-imidazolidin-2-one-hydro-chloride

Using thionyl chloride instead of hydrochloric acid gas.

Melting point: 217°-220° C.; R_(f) value: 0.29 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4)

(38) 1- 2-(4-quinuclidinyl)ethyl!-3- 4-2-(isopropyloxycarbonyl)ethyl!phenyl!-imidazolidin-2-one-hydrochloride

Using thionyl chloride instead of hydrochloric acid gas.

R_(f) value: 0.25 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(39) 1- 4-(4-cyano-4-piperidinyl)phenyl!-3-trans-4-(methoxycarbonyl)cyclohexyl!-imidazolidin-2-one-hydrochloride×H₂O

Melting point: >240° C.; R_(f) value: 0.54 (Reversed Phase Silica gel;methanol/5% aqueous saline solution=6:4); Calculated: C 59.41 H 7.15 N12.05 Cl 7.62; Found: 59.71 7.21 11.95 7.94; Mass spectrum: M⁺ =410

(40) 1- trans-4-(ethoxycarbonyl)cyclohexyl!-3-4-(4-piperidinyl)phenyl!-imidazolidin-2-one-hydrochloride

Using thionyl chloride instead of hydrochloric acid gas.

R_(f) value, 0.39 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 63.36 H 7.86 N 9.64 Cl 8.13; Found: 62.917.86 9.62 8.65

(41) 1- 4-(4-quinuclidinyl)phenyl!-3-trans-4-(ethoxycarbonyl)cyclohexyl!-imidazolidin-2-one-hydrochloride×0.5H₂ O

R_(f) value: 0.27 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 63.75 H 7.92 N 8.92 Cl 7.52; Found: 63.697.93 8.82 7.38; Mass spectrum: M⁺ =425

(42) 1- trans-4-(ethoxycarbonyl)cyclohexyl!-3-4-(4-piperidinyl)phenyl!-3H-imidazol-2-one-hydrochloride

Melting point: 260°-270° C.; R_(f) value: 0.50 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 63.65 H7.43 N 9.68; Found: 63.31 7.53 9.58; Mass.spectrum: M⁺ =397

(43) 1- trans-4-(ethoxycarbonyl)cyclohexyl!-3-4-(4-methyl-4-piperidinyl)phenyl!-imidazolidin-2-one-hydrochloride

R_(f) value: 0.43 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 64.05 H 8.06 N 9.34 Cl 7.88; Found: 63.808.28 9.24 7.89

EXAMPLE 7

1-(4-Amidinophenyl)-3- trans-4-2-(methoxycarbonyl)ethyl!cyclohexyl!-imidazolidin-2-one-hydrochloride

1.1 g of 1-(4-amidinophenyl) -3- trans-4- 2-(methoxycarbonyl)-ethyl!cyclohexyl!-3H-imidazol-2-one-hydrochloride in55 ml of methanol are hydrogenated for 3 hours with 1 g of palladium onactivated charcoal at ambient temperature under a hydrogen pressure of51 psi. The catalyst is removed by suction filtering, the filtrate isevaporated down and the residue is stirred with methylene chloride. Theproduct is suction filtered and dried.

Yield: 870 mg (79% of theory); R_(f) value: 0.52 (Reversed Phase Silicagel; methanol/10% aqueous saline solution=3:1); Calculated: C 58.74 H7.15 N 13.70; Found: 58.54 7.31 13.53

The following compounds are obtained analogously to Example 7:

(1) 1-(4-amidinophenyl)-3- cis-4-2-(methoxycarbonyl)ethyl!-cyclohexyl!-imidazolidin-2-one-hydrochloride×1water

R_(f) value: 0.52 (Reversed Phase Silica gel; methanol/10% aqueoussaline solution=3:1); Calculated: C 56.27 H 7.32 N 13.12; Found: 56.467.16 13.45

(2) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3- trans-4-2-(methoxycarbonyl)ethyl!cyclohexyl!imidazolidin-2-one

Melting point: 92°-94° C.; R_(f) value: 0.58 (Silica gel; ethyl acetate)

(3) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3- 4-2-(methoxycarbonyl)ethyl!phenyl!-cis-4,5-dimethylimidazolidin-2-one

Carried out in ethyl acetate at 80° C.

Rf value: 0.51 (Silica gel; cyclohexane/ethyl acetate=1:1)

(4) 1- 2-(methoxycarbonyl)-6-naphthyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride

Carried out in methanol/aqueous hydrochloric acid Rf value: 0.25(Reversed Phase Silica gel; methanol/5% aqueous saline solution=6:4)

(5) 1- 2-(methoxycarbonyl-1,2,3,4-tetrahydro-6-naphthyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride

Carried out in methanollaqueous hydrochloric acid

R_(f) value: 0.50 (Silica gel; methylene chloride/methanol/conc. aqueousammonia=5:1:0.2)

(6) 1- trans-4-(methoxycarbonyl)cyclohexyl!-3-4-(1-trifluoroacetyl-4-piperidinyl)phenyl!-imidazolidin-2-one

Melting point: 183°-185° C.; R_(f) value: 0.59 (Silica gel;cyclohexane/ethyl acetate=2:3)

(7) 1- trans-4-(methoxycarbonyl)cyclohexyl!3-4-(4-quinuclidinyl)phenyl!-imidazolidin-2-one-hydrochloride

Carried out in methanol/aqueous hydrochloric acid

R value: 0.38 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(8) 1- trans-4-(methoxycarbonyl)cyclohexyl!-3-4-(4-methyl-1-trifluoroacetyl-4-piperidinyl)phenyl!-imidazolidin-2-one

Carried out in ethyl acetate

Melting point: 158°-161° C.; R_(f) value: 0.50 (Silica gel;cyclohexane/ethyl acetate=1:1)

(9) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3- trans-4-(methoxycarbonyl)methyl!oxy!cyclohexyl!-imidazolidin-2-one

R_(f) value: 0.42 (Silica gel; ethyl acetate)

EXAMPLE 8

1-(4-Cyanophenyl)-3- trans-4-2-(methoxycarbonyl)ethyl!-cyclohexyl!-3H-imidazol-2-one

6.8 g of 4- (2,2-diethoxyethyl)amino!benzonitrile (melting point:75°-78° C., prepared from 4-aminobenzo-nitrile by reacting withbromoacetaldehyde-diethylacetal in the presence ofN-ethyl-diisopropylamine) and 6.81 g of trans-4-2-(methoxycarbonyl)-ethyl!cyclohexyl!-isocyanate (prepared from thecorresponding amine hydrochloride by reacting with phosgene) are stirredfor 8 hours at 65° C. and then for 2 hours at 100° C. After cooling, thereaction mixture is purified by chromatography over a silica gel columnusing cyclohexane/ethyl acetate (1:1). The product is stirred overnightin a mixture of 15 ml of dioxane and 10 ml of 2N hydrochloric acid. Theprecipitate is suction filtered and dried.

Yield: 1.9 g (19% of theory); Melting point: 136°-142° C.

The following compounds are obtained analogously to Example 8:

(1) 1-(4-cyanophenyl)-3- cis-4-2-(methoxycarbonyl)ethyl!-cyclohexyl!-3H-imidazol-2-one

R_(f) value: 0.40 (Silica gel; cyclohexane/ethyl acetate=1:1)

(2) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3- trans-4-2-(methoxycarbonyl)ethyl!cyclohexyl!-3H-imidazol-2-one

The N-2-(1-tert.butyloxycarbonyl-4-piperidinyl)-ethyl!-N-(2,2-diethoxyethyl)-amineused as amine is obtained by reacting 1-tert.butyloxycarbonyl-4-2-(methanesulfonyloxy)ethyl!-piperidine with aminoacetaldehyde-diethylacetal. The urea formation is carried out at ambient temperature,cyclisation by dry heating to 145° C.

R_(f) value: 0.34 (Silica gel; ethyl acetate)

(3) 1- trans-4-(methoxycarbonyl)cyclohexyl!-3-4-(1-trifluoroacetyl-4-piperidinyl)phenyl!-3H-imidazol-2-one

The N-(2,2-diethoxyethyl)-4-(1-trifluoroacetyl-4-piperidinyl)-anilineuse as amine R_(f) value: 0.90 (silica gel; cyclohexane/ethylacetate=1:3! is obtained by reacting 4-(1-trifluoroacetyl-4-piperidinyl)-aniline with bromoacetaldehyde-diethylacetal in thepresence of N-ethyl- diisopropylamine. Thetrans-4-(methoxycarbonyl)cyclohexyl-isocyanate used as isocyanate isobtained from the corresponding amine-hydrochloride by reacting withphosgene. Urea formation carried out at 100° C., cyclisation by dryheating to 125° C.

Melting point: 178°-179° C. R_(f) value: 0.36 (silica gel;cyclohexane/ethyl acetate=2:3)

(4) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3- trans-4-(methoxycarbonyl)-methyl!oxy!cyclohexyl!-3H-imidazol-2-one

The trans-4- (methoxycarbonyl)methyl!oxy!-cyclohexylisocyanate used asisocyanate is obtained by reaction of the correspondingamine-hydrochloride with phosgene. Urea formation effected at ambienttemperature, cyclization by dry heating at 160° C.

EXAMPLE 9

1-(1-Amino-1,2,3,4-tetrahydronaphthalin-6-yl)-3- 4-2-(methoxycarbonyl)ethyl!phenyl!-imidazolidin-2-one-hydrochloride

2.2 g of 1-(1-hydroxyimino-1,2,3,4-tetrahydronaphthalin-6-yl)-3- 4-2-(methoxycarbonyl)ethyl phenyl!imidazolidin-2-one, in a mixture of 100ml of methanol and 5 ml of methanolic hydrochloric acid, arehydrogenated for 5 hours at 50° C. under a hydrogen pressure of 3.4 barin the presence of 0.3 g of palladium on activated charcoal (10%palladium). The catalyst is suction filtered, the filtrate is evaporateddown and the residue is stirred with a little methanol. The product issuction filtered, washed with a little methanol and diethylether anddried.

Yield: 2.1 g (90% of theory); R_(f) value: 0.73 (silica gel;toluene/dioxane/methanol/conc. aqueous ammonia=20:50:20:5)

EXAMPLE 10

4- 4- 2-(Methoxycarbonyl)ethyl!phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-toluene-sulfonate×water

4 ml of trifluoroacetic acid are added to 1.3 g of 2-2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-4- 2-(methoxycarbonyl)ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one in 13 mlmethylene chloride and the mixture is stirred for 2 hours at ambienttemperature. The reaction mixture is evaporated down and the residue istaken up in methylene chloride. It is mixed with ice water, madeslightly alkaline with sodium hydroxide solution and the organic phaseis separated off. The organic phase is evaporated down, the residue istaken up in acetone and mixed with a solution of 500 mg ofp-toluenesulphonic acid-hydrate in acetone. Then diethylether is added,the mixture is stirred whilst cooling with ice and the precipitate issuction filtered and washed with acetone.

Yield: 760 mg (49% of theory); R_(f) value: 0.19 (silica gel;toluene/dioxane/methanol/conc. aqueous ammonia=20:50:20:5); Calculated:C 57.63 H 6.81 N 9.96 S 5.70; Found: 57.84 6.77 9.78 6.04

The following compounds are obtained analogously to Example 10:

(1) 1- 4- 2-(methoxycarbonyl)ethyl!phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride Isolated ashydrochloride

R_(f) value: 0.38 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(2) 1- 4- 2-(methoxycarbonyl)-1-pentyl!phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride

(3) 4- 4- 2-(methoxycarbonyl)-1-pentyl!phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride×0.5 water

Melting point: 132°-140° C.; Calculated: C 60.05 H 7.89 N 12.18 Cl 7.71;Found: 60.04 7.82 12.16 8.25

(4) 4- 4- 2-(methoxycarbonyl)-3-methyl-1-butyl!phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(5) 4- 4- 2-(methoxycarbonyl)-1-butyl!phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(6) 4- 4- 2-(methoxycarbonyl)-1-propyl!phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(7) 1- 4- 2-(methoxycarbonyl)ethyl!phenyl!-3-2-(4-piperidinyl)ethyl!-3,4,5,6-tetrahydro-1H-pyrimidin-2-one-hydrochloride

(8) 4- 4- 2-(methoxycarbonyl)ethyl!phenyl!-5-methyl-2-(1-piperazinyl)carbonylmethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(9) 4- 4- 2-(methoxycarbonyl)ethyl!phenyl!-5-methyl-2-2-(1-aza-4-cycloheptyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(10) 4- 4- 2-(methoxycarbonyl)ethyl!phenyl!-5-methyl-2-2-(1,4-diaza-1-cycloheptyl)ethyl!-4H-1,2,4-triazol-3-one-dihydrochloride

(11) 4- 4-2-(n-butylsulfonylamino)-2-(methoxycarbonyl)ethyl!phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(12) 4- 4-2-(methansulfonylamino)-2-(methoxycarbonyl)ethyl!phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(13) 4- 4-2-(acetylamino)-2-(methoxycarbonyl)-ethyl!-phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4- triazol-3-one-hydrochloride

(14) 4- 4- 2-(methoxycarbonyl)-1-octyl!phenyl!-5-methyl-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(15) 4- 4- 2-(methoxycarbonyl)ethyl!phenyl!-2-2-(4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride×0.5 H₂ O

Carried out with methanolic hydrochloric acid.

Melting point: 188°-191° C.; R_(f) value: 0.52 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 56.50 H6.99 N 13.87 Cl 8.78; Found: 56.79 6.93 13.76 8.83

(16) 2- 4- 2-(methoxycarbonyl)ethyl!phenyl!-5-2-(4-piperidinyl)ethyl!-3,4-dihydro-2H,5H-1,2,5-thiadiazole-1,1-dioxide-hydrochloride

Carried out with methanolic hydrochloric acid.

R_(f) value: 0.63 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(17) 1- 4- 2-(methoxycarbonyl)ethyl!phenyl!-3-(1-piperazinyl)carbonylmethyl!-imidazolidin-2-one-hydrochloride

Carried out with methanolic hydrochloric acid (the compound obtained wasdirectly converted into the compound of Example 1(31)).

(18) 1- 4- 2-(n-butylsulfonylamino)-2-(methoxycarbonyl)-ethyl!phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride

Carried out with methanolic hydrochloric acid.

Melting point: 208° C. (decomp.); R_(f) value: 0.43 (Reversed PhaseSilica gel; methanol/5% aqueous saline solution=6:4)

(19) 4- 4- 2-(methoxycarbonyl)ethyl!phenyl!-2-2-(1-piperazinyl)ethyl!-4H-1,2,4-triazol-3-one×2.1 HCl×0.3 H₂ O

Carried out with methanolic hydrochloric acid.

Melting point: 210°-213° C.; R_(f) value: 0.61 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 48.98 H6.32 N 15.87 Cl 16.87; Found: 48.96 6.36 15.88 16.99; Mass spectrum: M⁺=359

(20) 2-cyanimino-1- 4- 2-(methoxycarbonyl)ethyl!phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin×HCl×0.5 H₂ O

Carried out with trimethyliodosilane in methylene chloride and isolatedas the hydrochloride.

Melting point: 162°-165° C.; R_(f) value: 0.34 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 58.80 H7.28 N 16.33 Cl 8.27; Found: 58.70 7.22 16.18 8.51

(21) 1- 2-(1-aza-4-cycloheptyl)ethyl!-3- 4-2-(methoxycarbonyl)ethyl!phenyl!-imidazolidin-2-one-hydrochloridex 0.15water

Carried out with methanolic hydrochloric acid.

Melting point: 134°-136° C.; R_(f) value: 0.38 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 61.13 H7.89 N 10.18 Cl 8.59; Found: 61.18 7.89 10.29 8.38

(22) 1- trans-4- 2-(methoxycarbonyl)ethyl!cyclohexyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride

Carried out with methanolic hydrochloric acid in the presence oftetramethyl orthocarbonate.

Melting point: 190°-195° C. (decomp.); R_(f) value: 0.36 (Reversed PhaseSilica gel; methanol/5% aqueous saline solution=6:4); Calculated: C59.76 H 9.03 N 10.45 Cl 8.82; Found: 59.47 9.11 10.58 8.84

(23) 3- 4- 2-(methoxycarbonyl)ethyl!phenyl!-l-2-(4-piperidinyl)ethyl!-hydantoin-hydrochloride

Carried out with methanolic hydrochloric acid.

Melting point: 203°-205° C. (decomp.); R_(f) value: 0.57 (Reversed PhaseSilica gel; methanol/5% aqueous saline solution=6:4); Calculated: C58.60 H 6.88 N 10.25 Cl 8.65; Found: 58.40 6.95 10.14 8.55

(24) 1- 4- 2-(methoxycarbonyl)ethyl!phenyl!-3-2-(4-piperidinyl)ethyl!-4,5-dimethyl-3H-imidazol-2-one-hydrochloride

Carried out with methanolic hydrochloric acid.

R_(f) value: 0.33 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(25) 1- 4- 2-(methoxycarbonyl)ethyl!phenyl!-3-2-(4-piperidinyl)ethyl!-cis-4,5-dimethyl-imidazolidin-2-one-hydrochloride

Carried out with methanolic hydrochloric acid.

R_(f) value: 0.30 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(26) 1- 4- 2-(methoxycarbonyl)ethyl!phenyl!-3-2-(4-piperidinyl)ethyl!-hydantoin-hydrochloride

Carried out with methanolic hydrochloric acid.

Melting point: 186°-188° C.; R_(f) value: 0.41 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 58.60 H6.88 N 10.25 Cl 8.65; Found: 58.27 7.10 10.22 8.70

(27) 1- 4- 2-(methoxycarbonyl)ethyl!phenyl!-3-2-(4-piperidinyl)ethyl!-3H-benzimidazol-2-one-hydrochloride

Carried out with methanolic hydrochloric acid.

R_(f) value: 0.33 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(28) 1- 4- 2-(o-ethyl-phosphono)ethyl!phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one×0.9 HCl×1.1 H₂ O

Carried out with ethanolic hydrochloric acid.

R_(f) value: 0.42 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 51.98 H 7.65 N 9.09 Cl 6.90; Found: 51.747.43 9.08 6.51; Mass spectrum: (M+H)⁺ =410

(29) 1- 4-(ethoxycarbonyl)-1-piperidinyl!carbonyl-methyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-trifluoroacetate

R_(f) value: 0.57 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(30) 1- 4- 2-(methoxycarbonyl)ethenyl!-2-fluoro-phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride

Carried out with methanolic hydrochloric acid.

Melting point: 175°-180° C.; R_(f) value: 0.30 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4)

EXAMPLE 11

1- 4-(Aminomethyl)cyclohexyl!-3- 4-2-(methoxycarbonyl)-ethyl!-phenyl!-imidazolidin-2-one-hydrochloride

500 mg of 1-(4-cyanocyclohexyl)-3- 4-2-(methoxycarbonyl)ethyl!-phenyl!-3H-imidazol-2-one are hydrogenated ina mixture of 20 ml of methanol and 1 ml of methanolic hydrochloric acidin the presence of 500 mg of palladium on activated charcoal (10%palladium) at ambient temperature under a hydrogen pressure of 5 bar.The catalyst is filtered off and the filtrate is evaporated down. Theresidue is triturated with acetone, suction filtered and washed withacetone and petroleum ether.

Yield: 110 mg (20% of theory); R_(f) value: 0.46 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4)

The following compounds are obtained analogously to Example 11:

(1) 2- 4-(aminomethyl)phenyl!-4- 4-2-(ethoxycarbonyl)-1-propyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

Carried out in ethanol

Melting point: 194°-197° C. R_(f) value: 0.54 (Reversed Phase Silicagel; methanol/10% aqueous saline solution=3:1)

(2) 1-(2-aminomethyl-1,2,3,4-tetrahydro-6-naphthyl)-3-trans-4-(methoxycarbonyl)cyclohexyl!-imidazolidin-2-one-hydrochloride

Melting point: 323°-327° C. (decomp.); R_(f) value: 0.35 (Reversed PhaseSilica gel; methanol/5% aqueous saline solution=6:4)

(3) 1- 4-(aminomethyl-bicyclo 2.2.2!octan-1-yl!-3- 4-2-(methoxycarbonyl)ethyl!phenyl!-imidazolidin-2-one-hydrochloride

Melting point: 303°-306° C. (decomp.); R_(f) value: 0.27 (Reversed PhaseSilica gel; methanol/5% aqueous saline solution=6:4)

(4) 1-(5-aminopentyl)-3- 4-2-(methoxycarbonyl)ethyl!phenyl!-imidazoldin-2-one-hydrochloride

Melting point: 234°-236 C.; Calculated: C 58.45 H 7.63 N 11.36 Cl 9.58;Found: 58.17 7.58 11.50 9.66

(5) 1- 4- (2-aminoethyl)oxy!phenyl!-3-trans-4-(methoxycarbonyl)cyclohexyl!-imidazolidin-2-one-hydrochloride

Carried out in methanol/0.1N HCl

R_(f) value: 0.47 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

EXAMPLE 12

1-(4-Cyanocyclohexyl)-3- 4-2-(methoxycarbonyl)ethyl!phenyl!-3H-imidazol-2-one

1.8 g of potassium tert.butoxide in 50 ml of tert.butanol are addeddropwise at -12° to -16° C. to 2.7 g of 3- 4-2-(methoxycarbonyl)ethyl!phenyl!-1-(4-oxocyclohexyl)-3H-imidazol-2-oneand 2.0 g of p-toluenesulfonyl-methyl-isocyanide in 60 ml ofethyleneglycol dimethylether. After 45 minutes the cooling bath isremoved and stirring is continued for a further 2 hours. The reactionmixture is neutralised with hydrochloric acid and then evaporated down.The residue is dissolved in chloroform, washed 3 times with water, driedand the organic phase is evaporated down. The residue is purified bychromatography over a silica gel column using cyclohexane/ethyl acetate(1:1).

Yield: 500 mg (18% of theory); Melting point: 177°-180° C.; R_(f) value:0.24 (silica gel; cyclohexane/ethyl acetate=3:7)

EXAMPLE 13

1-(4-Amidinophenyl)-3- 4-2-(isopropyloxycarbonyl)-ethyl!-phenyl!-imidazolidin-2-one×1.1 hydrogenchloride

Hydrochoric gas is introduced into a mixture of 400 mg of1-(4-amidinophenyl)-3- 4-2-(methoxycarbonyl)ethyl!phenyl!-imidazolidin-2-one-hydrochloride and300 ml of isopropanol and then refluxed for 1.5 hours. After cooling,the mixture is evaporated down and the residue is triturated withacetone and suction filtered. The product is washed with acetone anddiethylether and dried.

Yield: 400 mg (92% of theory); R_(f) value: 0.32 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=3:2); Calculated: C 60.80 H6.29 N 12.89 Cl 8.97; Found: 60.73 6.29 12.86 8.86

The following compounds are obtained analogously to Example 13:

(1) 1-(4-amidinophenyl)-3- 4-2-(cyclohexyloxycarbonyl)ethyl!phenyl!-imidazolidin-2-one-hydrochloride

R_(f) value: 0.07 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(2) 1-(4-amidinophenyl)-3- trans-4-2-(cyclohexyloxycarbonyl)ethyl!cyclohexyl!-imidazolidin-2,4-dione-hydrochloride×cyclohexanol

R_(f) value: 0.11 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 62.98 H 8.01 N 9.48 Cl 6.00; Found: 63.057.97 9.79 6.40

(3) 2-(4-amidinophenyl)-4- 4-2-(cyclohexyloxycarbonyl)-1-propyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

R_(f) value: 0.12 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(4) 1-(4-amidinophenyl)-3- 4-2-(n-butylsulfonylamino)-2-(cyclohexyloxycarbonyl)-ethyl!phenyl!-imidazolidin-2-one-hydrochloride

EXAMPLE 14

1-(4-Cyanophenyl)-3- trans-4-2-(methoxycarbonyl)ethyl!cyclohexyl!-imidazolidin-2,4-dione

5.5 g of N-(4-cyanophenyl)-N-(methoxycarbonylmethyl)-N'- trans-4-2-(methoxycarbonyl)ethyl!cyclohexyl!-urea are heated to 180° C. for 4.5hours in vacuo. After cooling, 10 ml of ethyl acetate are added, themixture is briefly heated to boiling and then cooled in an ice bath. Thesolid matter is suction filtered and washed with a little ethyl acetate.

Yield: 3.8 g (75% of theory);

Melting point: 207°-208° C., R_(f) value: 0.75 (Silica gel; methylenechloride/ethyl acetate=3:1)

EXAMPLE 15

1- 4-(2-Carboxyethyl)phenyl!-3-2-(1-methyl-4-piperidinyl)-ethyll-imidazolidin-2-one×1.1 HCl

900 mg of 1- 4- 2-(methoxycarbonyl)ethyl!phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride, 600 mg offormic acid and 250 mg of aqueous formaldehyde solution (37%) arestirred for 4 hours at 70°-80° C. 1.1 ml of 2N sodium hydroxide solutionand 0.2.ml of aqueous formaldehyde solution (37%) are added and themixture is stirred for a further 3 hours at 70°-80C. It is evaporateddown, the residue is mixed with 3ml of hydrochloric acid and stirred for1 hour at 70° C. It is cooled, acetone is added and the precipitate isfiltered off. The filtrate is evaporated down and stirred with acetone.The solid substance is suction filtered and dried. The residue isdecocted with 70 ml of methylene chloride, then filtered off and thefiltrate is evaporated down. This procedure is repeated with 70 ml ofchloroform. The combined evaporation residues are stirred with acetone,the solid matter is suction filtered, washed and dried.

Yield: 400 mg (46% of theory); Melting point: 220° C. (decomp.); R_(f)value: 0.45 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 60.12 H 7.59 N 10.52 Cl 9.76; Found: 60.047.64 10.30 9.63

The following compounds are obtained analogously to Example 15:

(1) 4- 4-(2-carboxyethyl)phenyl!-5-methyl-2-2-(1-methyl-4-piperidinyl)ethyl!-4H-1,2,4-triazol-3-one-hydrochloride

(2) 1-(trans-4-carboxycyclohexyl)-3-4-(1-methyl-4-piperidinyl)phenyl!-imidazolidin-2-one×0.95 HCl×0.5 H₂ O

The reaction is carried out with the carboxylic acid.

R_(f) value: 0.49 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 61.57 H 7.74 N 9.79 Cl 7.84; Found: 61.677.77 9.92 7.70

EXAMPLE 16

1- 4-4-(Methoxycarbonyl)butyl!phenyl!-3-(4-piperidinyl)-imidazolidin-2-one-hydrochloride

1.7 g of 1-(1-benzyl-4-piperidinyl)-3- 4-4-(methoxy-carbonyl)-butyl!phenyl!-imidazolidin-2-one (also containingtriphenylphosphineoxide and diethyl hydrazine-1,2-dicarboxylate) arehydrogenated in 50 ml of methanol in the presence of 0.5 g of palladiumon activated charcoal (10% palladium) at ambient temperture under ahydrogen pressure of 50 psi. After 4.5 hours, a further 0.5 g ofpalladium catalyst are added and the mixture is hydrogenated for another8 hours. The catalyst is filtered off, the filtrate is evaporated down,mixed with acetone and etherial hydrochloric acid and evaporated downonce more. After stirring with acetone the product is suction filteredand dried.

Yield: 150 mg, R_(f) value: 0.22 (Reversed Phase silica gel; Methanol/5%aqueous saline solution=6:4)

EXAMPLE 17

1-(trans-4-Carboxycyclohexyl)-3-4-(4-piperidinyl)phenyl!-imidazolidin-2-one-hydrochloride

940 mg of 1- trans-4-(ethoxycarbonyl)cyclohexyl!-3-4-(1-trifluoroacetyl-4-piperidinyl)phenyl!-imidazolidin-2-one (alsocontaining diethyl hydrazine-1,2-carboxylate), 10 ml of glacial aceticacid, 10 ml of water and 10 ml of concentrated hydrochloric acid areheated to 90° C. for 5.5 hours. Then the mixture is cooled, left tostand at ambient temperature for 2 days, evaporated down, mixed twicewith water and again evaporated down and then stirred for 1.5 hours with10 ml of water in an ice bath. The resulting precipitate is suctionfiltered, dried and stirred overnight with 20 ml oftert.butyl-methylether. The product is suction filtered, washed withtert.butyl-methylether and dried.

Yield: 47 mg, Melting point: 315°-320° C. (decomp.); R_(f) value: 0.55(Reversed Phase silica gel; Methanol/5% aqueous saline solution=6:4);Mass spectrum: M⁺ =371

The following compounds are obtained analogously to Example 17:

(1) 1-(4-carboxybutyl)-3-4-(4-piperidinyl)phenyl!imidazolidine-2-one-hydrochloride

Melting point: 245°-248° C. (decomp.); R_(f) value: 0.49 (Reversed PhaseSilica gel; methanol/5% aqueous saline solution 32 6:4); Calculated: C59.75 H 7.39 N 11.00 Cl 9.28; Found: 59.38 7.41 10.84 9.02

(2) 1-(4-carboxyphenyl)-3-4-(4-piperidinyl)phenyl!imidazolidin-2-one-hydrochloride×H₂ O

Melting point: >250° C.; Calculated: C 60.09 H 6.24 N 10.01 Cl 8.44;Found: 60.31 6.25 10.27 8.52; Mass spectrum: M⁺ =365

EXAMPLE 18

1- 4-(2-Carboxyethyl)cyclohexyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride

400 mg of 1- 4-(2-carboxyethyl)phenyl!-3-2-(4-piperidinyl)-ethyl!-imidazolidin-2-one-hydrochloride in 10 ml ofglacial acetic acid are hydrogenated with 50 mg of platinum(IV) oxideunder a hydrogen pressure of 3.4 bar for 13 hours at 60° C. The reactionmixture is filtered, the filtrate is evaporated down, taken up in amixture of dilute hydrochloric acid and tetrahydrofuran, filtered andevaporated down again. The product is stirred with tetrahydrofuran andthen with acetone and diethylether, suction filtered, washed withacetone and diethylether and dried.

Yield: 244 mg (58 % of theory), R_(f) value: 0.49 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4)

The following compounds are obtained analogously to Example 18:

(1) 1- 4-(2-carboxyethyl)cyclohexyl!-3-2-(4-piperidinyl)-ethyl!-3a,4,5,6,7,7a-hexahydro-benzimidazol-2-one×1.6HCl×1.8 H₂ O

R_(f) value: 0.40 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 55.66 H 8.98 N 8.47 Cl 11.43; Found: 55.648.69 8.66 11.46

(2) 1-(trans)-4-carboxycyclohexyl)-3-4-(4-piperidinyl)cyclohexyl!-imidazolidin-2-one-hydrochloride

Carried out in water with Rhodium/Platinum catalyst

R_(f) value: 0.55 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Mass spectrum: M⁺ =377

EXAMPLE 19

1- 4-2-(n-Butylsulfonylamino)-2-(methoxycarbonyl)ethyl!-phenyl!-3-(4-cyanophenyl)-imidazolidin-2-one

At ambient temperature, 495 mg of diethyl azodicarboxy-late in 2 ml ofacetonenitrile are rapidly added dropwise to 1.3 g of N- 4-2-(n-butylsulfonylamino)-2-(methoxycarbonyl)-ethyl!phenyl!-N'-4-(cyanophenyl)-N-(2-hydroxyethyl)-ureaand 0.71 g of triphenylphosphine in 8 ml of acetonitrile and then themixture is stirred for 3.5 hours at ambient temperature. The precipitateis suction filtered, washed with a little acetonitrile and methanol andthen dried.

Yield: 1.05 g (84% of theory), Melting point: 181°-183° C.

The following compounds are obtained analogously to Example 19:

(1) 1-(4-cyanophenyl)-3- 4-2-(methoxycarbonyl)ethyl!phenyl!-imidazolidin-2-one

Melting point: 162°-164° C.

(2) 1- trans-4-(ethoxycarbonyl)cyclohexyl!-3-4-(1-trifluoroacetyl-4-piperidinyl)phenyl!-imidazolidin-2-one

Also contains diethyl hydrazine-1,2-dicarboxylate

R_(f) value: 0.60 (Silica gel; cyclohexane/ethyl acetate=2:1)

(3) 1- 4-(ethoxycarbonyl)phenyl!-3-4-(1-trifluoroacetyl-4-piperidinyl)phenyl!-imidazolidin-2-one

Melting point: 235°-239° C. (decomp.)

(4) 1- 4-(4-cyano-1-trifluoroacetyl-4-piperidinyl)phenyl!-3-trans-4-(methoxycarbonyl)cyclohexyl!imidazolidin-2-one

Carried out in dimethylformamide at 50° C.

R_(f) value: 0.70 (Silica gel; ethyl acetate/cyclohexane=5:1)

(5) 1- trans-4-(methoxycarbonyl)cyclohexyl!-3-4-(1-trifluoroacetyl-4-piperidinyl)phenyl!-imidazolidin-2-one

Carried out in dimethylformamide at 50° C.

R_(f) value: 0.77 (Silica gel; ethyl acetate/cyclohexane=5:1)

(6) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3- 4-2-(n-butylsulfonylamino)-2-(methoxycarbonyl)ethyl!phenyl!-imidazolidin-2-one

Melting point: 124°-126° C.; R_(f) value: 0.42 (Silica gel; methylenechloride/ethyl acetate=7:3)

(7) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-2-cyanimino-3- 4-2-(methoxycarbonyl)ethyl!phenyl!imidazolidine

R_(f) value: 0.27 (Silica gel; cyclohexane/ethyl acetate=3:7)

(8) 1- 2-(1-tert.butyloxycarbonyl-1-aza-4-cycloheptyl)ethyl!-3- 4-2-(methoxycarbonyl)ethyl!phenyl!imidazolidin-2-one

R_(f) value: 0.38 (Silica gel; cyclohexane/ethyl acetate=1:1)

(9) 1-(1-benzyl-4-piperidinyl)-3- 4-4-(methoxy-carbonyl)-butyl!phenyl!-imidazolidin-2-one

Also contains triphenylphosphine oxide and diethylhydrazine-1,2-dicarboxylate.

R_(f) value: 0.46 (Silica gel; methylene chloride/ethylacetate/methanol=20:0.5:1.5)

(10) 1- 4-2-(O,O'-diethylphosphono)ethyl!phenyl!-3-(2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!imidazolidin-2-one

R_(f) value: 0.35 (Silica gel; methylenechloride/ethyl-acetate/methanol=20:1:1)

(11) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3- 2-cyano-4-2-(methoxycarbonyl)ethyl!phenyl!-imidazolidine-2-one

R_(f) value: 0.63 (Silica gel; methylene chloride/ethyl acetate=1:1)

EXAMPLE 20

1- 4- (1-Acetoxyethyl)oxycarbonylamidino!phenyl!-3- 4-2-(isopropyloxycarbonyl)ethyl!phenyl!-imidazolidin-2-one

220 mg of 1-(4-amidinophenyl)-3- 4-2-(isopropyloxycarbonyl)-ethyl!phenyl!-imidazolidin-2-one-hydrochloride,190 mg of (1-acetoxyethyl)-(4-nitrophenyl)carbonate and 168 mg ofN-ethyl-diisopropylamine are stirred in 20 ml of methylene chloride for4 hours at ambient temperature. The reaction mixture is diluted with alittle methylene chloride and then washed with ice water, twice with0.2N sodium hydroxide solution and again with ice water. The organicphase is dried, evaporated down and the residue is stirred withtert.butylmethylether. The product is suction filtered, washed with alittle tert.butylmethyl-ether and dried.

Yield: 250 mg (95 % of theory), R_(f) value: 0.47 (Silica gel; methylenechloride/methanol=95:5); Calculated: C 61.82 H 6.15 N 10.68; Found:61.69 6.21 10.63

The following compounds are obtained analogously to Example 20:

(1) 1- 4- (acetoxymethyl)oxycarbonylamidino!phenyl!-3- 4-2-(isopropyloxycarbonyl)ethyl!phenyl!-imidazolidin- 2-one

(2) 2- 4- (1-acetoxyethyl)oxycarbonylamidino!phenyl!-4- 4-2-(cyclohexyloxycarbonyl)ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one

(3) 2- 4- (acetoxymethyl)oxycarbonylamidino!phenyl!-4- 4-2-(cyclohexyloxycarbonyl)ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one

(4) 4- 4- 2-(methoxycarbonyl)ethyl!phenyl!-5-methyl-2- 4-(pivaloyloxymethyl)oxycarbonylamidino!phenyl!-4H-1,2,4-triazol-3-one

(5) 4- 4- 2-(cyclohexyloxycarbonyl)ethyl!phenyl!-2-4-(methoxycarbonylamidino)phenyl!-5-methyl-4H-1,2,4-triazol-3-one

(6) 4- 4- 2-(cyclohexyloxycarbonyl)ethyl!phenyl!-2-4-(ethoxycarbonylamidino)phenyl!-5-methyl-4H-1,2,4-triazol-3-one

(7) 2- 4-(benzyloxycarbonylamidino)phenyl!-4- 4-2-(methoxycarbonyl)ethyl)phenyl!-5-methyl-4H-1,2,4-triazol-3-one

(8) 2- 4- (1-acetoxyethyl)oxycarbonylamidino!phenyl!-4- 4-2-(isopropyloxycarbonyl)ethyl!phenyl!-5-methyl-4H-1,2,4,triazol-3-one

Melting point: from 167° C. (decomp.); R_(f) value: 0.39 (Silica gel;methylene chloride/methanol=95:5); Calculated: C 60.33 H 5.81 N 13.03;Found: 60.25 5.86 13.25

(9) 2- 4- (acetoxymethyl)oxycarbonylamidino!phenyl!-4- 4-2-(isopropyloxycarbonyl)ethyl!phenyl!-5-methyl-4H-1,2,4,triazol-3-one

Melting point: 152°-153° C. (decomp.); R_(f) value: 0.45 (Silica gel;methylene chloride/methanol=95:5); Calculated: C 59.65 H 5.58 N 13.38;Found: 59.25 5.65 13.51

(10) 1- trans-4-(methoxycarbonyl)cyclohexyl!-3-4-(1-benzyloxycarbonyl-4-piperidinyl)phenyl!-imidazolidin-2-one

Melting point: 145°-148° C.; R_(f) value: 0.75 (Silica gel; methylenechloride/methanol=9:1)

(11) 1-(trans-4-carboxycyclohexyl)-3-4-(1-benzyloxycarbonyl-4-cyano-4-piperidinyl)phenyl!-imidazolidin-2-one

Carried out in water with sodium hydroxide solution as base.

Melting point: 238°-240° C.; R_(f) value: 0.42 (Silica gel; methylenechloride/methanol=9:1)

EXAMPLE 21

1- trans-4-1-(Cyclohexyloxycarbonyloxy)ethyl!oxy-carbonyl!-cyclohexyl!-3-(4-(1-benzyloxycarbonyl-4-piperidinyl)phenyl!-imidazolidin-2-one

2.0 g of 1-(trans-4-carboxycyclohexyl)-3-4-(1-benzyloxycarbonyl-4-piperidinyl)phenyl!-imidazolidin-2-one, 4.5 gof (1-chloroethyl)-cyclohexylcarbonate and 0.2 g of sodium iodide in 10ml of dimethylsulfoxide are stirred for 1 hour at ambient temperature.1.1 g of potassium carbonate are added and the mixture is stirred for 16hours at 60° C. After cooling the reaction mixture is poured onto 100 mlof water, to which 1 ml of glacial acetic acid has been added. Themixture is extracted 3 times with ethyl acetate, the combined organicphases are washed with saline solution, dried and evaporated down. Theresidue is purified by chromatography over a silica gel column withcyclohexane/ethyl acetate (1:1).

Yield: 0.8 g (30 % of theory), R_(f) value: 0.54 (Silica gel;cyclohexane/ethyl acetate=1:1); Mass spectrum: M⁺ =675

The following compounds are obtained analogously to Example 21:

(1) 2- 4-(benzyloxycarbonylamidino)phenyl!-5-methyl-4- 4- 2-(pivaloyloxymethyl)oxycarbonyl!ethyl!phenyl!-4H-1,2,4-triazol-3-one

Alkylating agent: chloromethyl pivalate

(2) 2- 4-(benzyloxycarbonylamidino)phenyl!-4- 4- 2-1-(cyclohexyloxycarbonyloxy)ethyl!oxycarbonyl!ethyl!-phenyl!-5-methyl-4H-1,2,4-triazol-3-one

(3) 1- 4-(1-benzyloxycarbonyl-4-piperidinyl)phenyl!-3- trans-4-(pivaloyloxymethyl)oxycarbonyl!cyclohexyl!imidazolidin-2-one

Alkylating agent: chloromethyl pivalate

R_(f) value: 0.50 (Silica gel; cyclohexane/ethyl acetate=1:1); Massspectrum: M⁺ =619

(4) 1- 4-(1-benzyloxycarbonyl-4-piperidinyl)phenyl!-3- trans-4-1-(ethyloxycarbonyloxy)ethyl!oxycarbonyl!-cyclohexyl!-imidazolidin-2-one

Alkylating agent: (1-chloroethyl)-ethylcarbonate

R_(f) value: 0.40 (Silica gel; cyclohexane/ethyl acetate=1:1)

EXAMPLE 22

1- trans-4-(5-Indanyloxycarbonyl) cyclohexyl!-3-4-(4-piperidinyl)phenyl!-imidazolidin-2-one×H₂ O×0.85 HCl

1.0 g of 1- trans-4-(5-indanyloxycarbonyl)cyclohexyl!-3-4-(1-benzyloxycarbonyl-4-piperidinyl)phenyl!imidazolidin-2-one arehydrogenated for 2.5 hours in a mixture of 20 ml of tetrahydrofuran, 2ml of water and 1.6 ml of 1N hydrochloric acid in the presence of 0.2 gof palladium on activated charcoal at ambient temperature under ahydrogen pressure of 50 psi. A further 0.2 g of catalyst and 1 mil of 1Nhydrochloric acid are added and the mixture is hydrogenated for afurther 2 hours. Then the catalyst is removed by suction filtering andthe filtrate is washed several times with tetrahydrofuran/water/1Nhydrochloric acid (20:1:1). The combined filtrates are adjusted to a pHof 7 with 1N sodium hydroxide solution and evaporated down. Theresulting suspension is stirred for 1 hour in an ice bath. The solidmatter is suction filtered, washed with a little ice water and dried.

Yield: 460 mg (54 % of theory), R_(f) value: 0.40 (Silica gel; methylenechloride/methanol/conc. aqueous ammonia =4:1:0.2); Calculated: C 67.14 H7.48 N 7.83 Cl 5.62; Found: 67.29 7.59 7.90 5.81; Mass spectrum: M⁺ =487

The following compounds are obtained analogously to Example 22:

(1) 2-(4-amidinophenyl)-5-methyl-4- 4- 2- (pivaloyloxymethyl)oxycarbonyl!ethyl!phenyl!-4H-1, 2,4-triazol-3-one-hydrochloride

(2) 2-(4-amidinophenyl)-4- 4- 2-1-(cyclohexyloxycarbonyloxy)ethyl!oxycarbonyl!ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one-hydrochloride

(3) 1- 4-(4-piperidinyl)phenyl!-3- trans-4-(pivaloyloxymethyl)oxycarbonyl!cyclohexyl!-imidazolidin-2-one-hydrochloride

R_(f) value: 0.52 (Silica gel; methylene chloride/methanol/conc. aqueousammonia=4:1:0.2); Mass spectrum: M⁺ =485

(4) 1- trans-4- 1-(ethyloxycarbonyloxy)ethyl!oxycarbonyl!-cyclohexyl!-3-4-(4-piperidinyl)phenyl!imidazolidin-2-one-hydrochloride

R_(f) value: 0.50 (Silica gel; methylene chloride/methanol/conc. aqueousammonia=4:1:0.2)

(5) 1- trans-4-1-(cyclohexyloxycarbonyloxy)ethyl!oxycarbonyl!cyclohexyl!-3-4-(4-piperidinyl)phenyl!imidazolidin-2-one-hydrochloride

R_(f) value: 0.45 (Silica gel; methylene chloride/methanol/conc. aqueousammonia=4:1:0.2); Mass spectrum: M⁺ =541

(6) 1- trans-4-(5-indanyloxycarbonyl)cyclohexyl!-3-4-(4-cyano-4-piperidinyl)phenyl!-imidazolidin-2-one

R_(f) value: 0.30 (Silica gel; methylene chloride/methanol/conc. aqueousammonia=4:1:0.2); Mass spectrum: M⁺ =512

EXAMPLE 23

2- 2-(1-tert.Butyloxycarbonyl-4-piperidinyl)ethyl!-4- 4-2-(methoxycarbonyl)ethyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one

To 1.1 g of 4- 4-2-(methoxycarbonyl)ethyl!phenyl!-5-methyl-4H-1,2,4,-triazol-3-one in 6ml of dimethyl-formamide are added 500 mg of potassium tert.butoxide andthe mixture is stirred for 30 minutes at ambient temperature. It is thencooled in an ice bath and mixed with 1.3 g of 1-tert.butyloxycarbonyl-4-2-(methane-sulfonyloxy)ethyl!piperidine. The mixture is then stirrredfor 2 hours at ambient temperature. Ice water is added to the reactionmixture which is made neutral with citric acid solution. It is decantedoff and the residue is digested with diethylether. The product issuction filtered, washed with water and dried.

Yield: 1.38 g (69% of theory), R_(f) value: 0.61 (Silica gel; ethylacetate)

The following compounds are obtained analogously to Example 23:

(1) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3- 4-2-(methoxycarbonyl)ethyl!phenyl!-imidazolidin-2-one

Carried out in dimethylformamide with sodium hydride.

R_(f) value: 0.41 (Silica gel; cyclohexane/ethyl acetate=1:1)

(2) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3- 4-2-(methoxycarbonyl)-1-pentyl!phenyl!-imidazolidin-2-one

(3) 2- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-4- 4-2-(methoxycarbonyl)-1-pentyl!phenyll-5-methyl-4H-1,2,4-triazol-3-one

R_(f) value: 0.73 (Silica gel; ethyl acetate); Calculated: C 65.34 H8.22 N 10.89; Found: 65.54 8.32 10.75

(4) 2- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-4- 4-2-(methoxycarbonyl)-3-methyl-1-butyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one

(5) 2- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-4- 4-2-(methoxycarbonyl)-1-butyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one

(6) 2- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-4- 4-2-(methoxycarbonyl)-1-propyl!phenyl!-5-methyl-4H-1,2,4-triazol-3-one

(7) 1- 4-(methoxycarbonyl)butyl!-3-4-(1-trifluoroacetyl-4-piperidinyl)phenyl!-imidazolidin-2-one

Carried out in dimethylformamide with sodium hydride.

Melting point: 115°-117° C.; R_(f) value: 0.73 (Silica gel; ethylacetate/cyclohexane=4:1)

(8) 1- 4-(4-cyano-1-trifluoroacetyl-4-piperidinyl)phenyl!-3-4-(methoxycarbonyl)butyl!-imidazolidin-2-one

Carried out in dimethylformamide with sodium hydride.

R_(f) value: 0.49 (Silica gel; ethyl acetate/cyclohexane=7:3)

(9) 2- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-4- 4-2-(methoxycarbonyl)ethyl!phenyl!-4H-1,2,4-triazol-3-one

Melting point: 139°-141° C.; R_(f) value: 0.58 (Silica gel; ethylacetate/cyclohexane=7:3)

(10) 2- 2-(1-tert butyloxycarbonyl-4-piperidinyl)ethyl!-5-(4-2-(methoxycarbonyl)ethyl!phenyl!-3,4-dihydro-2H,5H-1,2,5-thiadiazole-1,₁-dioxide

Carried out in dimethylformamide with sodium hydride.

R_(f) value: 0.41 (Silica gel; cyclohexane/ethyl acetate=1:1)

(11) 1- (1-tert.butyloxycarbonyl-4-piperazinyl)carbonylmethyl!-3- 4-2-(methoxycarbonyl)ethyl!phenyl!imidazolidin-2-one

Carried out in dimethylforminamide with sodium hydride. (The(1-tert.butyloxycarbonyl-4-piperazinyl)-carbonylmethylchloride used asalkylating agent is obtained from 1-benzyl-piperazine by reacting withdi-tert.butylpyrocarbonate, subsquently hydrogenating with palladium onactivated charcoal and then reacting with chloroacetylchloride).

Melting point: 185°-187° C.; R_(f) value: 0.44 (Silica gel; methylenechloride/ethyl acetate=1:1); Calculated: C 60.74 H 7.22 N 11.81; Found:60.70 7.31 11.87

(12) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3- 4-2-(methoxycarbonyl)ethyl!phenyl!-3,4,5,6-tetrahydro-1H-pyrimidin-2-one

Carried out in dimethylformamide with sodium hydride.

R_(f) value: 0.36 (Silica gel; methylene chloride/methanol=200:3)

(13) 2- 2-(1-tert.butyloxycarbonyl-4-piperazinyl)ethyl!-4- 4-2-(methoxycarbonyl)ethyl!phenyl!-4H-1,2,4-triazol-3-one

The alkylating agent used (melting point: 238°-240° C.) is obtained from1-(2-hydroxyethyl)piperazine by reacting with di-tert.butylpyrocarbonate and subsequently reacting with methanesulphonic acidchloride in the presence of triethylamine.

Melting point: 128°-130° C.; R_(f) value: 0.35 (Silica gel; ethylacetate)

(14) 1- 4- 2-(methoxycarbonyl)ethyl!phenyl!-3-2-(2,2,6,6-tetramethyl-4-piperidinyl)ethyl!-imidazolidin-2-one

Carried out in dimethylformamide with sodium hydride.

Melting point: 127°-129° C.; R_(f) value: 0.32 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 69.36 H8.97 N 10.11; Found: 69.21 9.07 10.03

(15) 1- 4- 2-(methoxycarbonyl)ethyl!phenyl!-3-2-(4-quinuclidinyl)ethyl!-imidazolidin-2-one×BH₃

Carried out in dimethylformamide with sodium hydride.

Melting point: 173°-176° C.; R_(f) value: 0.56 (Silica gel;cyclohexane/ethyl acetate=2:8)

(16) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3- 4-2-(methoxycarbonyl)ethyl!phenyl!-hydantoin

Carried out in dimethylformamide with sodium hydride.

Melting point: 104°-106° C.; R_(f) value: 0.30 (Silica gel;cyclohexane/ethyl acetate=1:1); Calculated: C 63.41 H 7.45 N 8.87;Found: 63.66 7.49 8.95

(17) 3- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-1- 4-2-(methoxycarbonyl)ethyl!phenyl!-4,5-dimethyl-3H-imidazol-2-one

Carried out in dimethylformamide with sodium hydride.

Melting point: 123°-125° C.; R_(f) value: 0.39 (Silica gel;cyclohexane/ethyl acetate=2:8)

(18) 3- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-1- 4-2-(methoxycarbonyl)ethyl!phenyl!-hydantoin

Carried out in dimethylformamide with sodium hydride.

Melting point: 97°-99° C.; R_(f) value: 0.46 (Silica gel;cyclohexane/ethyl acetate=1:1)

(19) 1- 4- 2-(methoxycarbonyl)ethyl!phenyl!-3-2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3H-benzimidazol-2-one

Carried out in dimethylformamide with sodium hydride.

R_(f) value: 0.33 (Silica gel; cyclohexane/ethyl acetate=6:4)

(20) 1- 4- 2-(methoxycarbonyl)ethyl!phenyl!-3-2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-4-methyl-imidazolidin-2-one

Carried out in dimethylformamide with sodium hydride.

R_(f) value: 0.58 (Silica gel; cyclohexane/ethyl acetate=1:1)

(21) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3-4-(ethoxycarbonyl)-1-piperidinyl!carbonylmethyl)imidazolidin-2-one

Carried out in dimethylformamide with sodium hydride. The alkylatingagent ( 4-(ethoxycarbonyl)-1-piperidinyl!-carbonyl!-methyl-chlorideR_(f) value: 0.35 (Silica gel; cyclohexane/ethyl acetate=1:1)! isobtained by reacting ethyl piperidine-4-carboxylate withchloracetylchloride in the presence of triethylamine.

(22) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl-3- 4-2-(methoxycarbonyl)ethenyl!-2-fluoro-phenyl!-imidazolidin-2-one

Melting point: 120°-122° C.; R_(f) value: 0.70 (Silica gel;cyclohexane/ethyl acetate=1:3)

(23) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3- 4-2-(methoxycarbonyl)ethenyl!-2-trifluoromethyl-phenyl!imidazolidin-2-one

R_(f) value: 0.54 (Silica gel; cyclohexane/ethyl acetate=1:2)

(24) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3- 4-2-(methoxycarbonyl)ethenyl!-2-methyl-phenyl!-imidazolidin-2-one

R_(f) value: 0.60 (Silica gel; cyclohexane/ethyl acetate=1:2)

(25) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3- 4-2-(methoxycarbonyl)ethenyl!phenyl!-imidazolidin-2-one

Melting point: 148°-149° C.; R_(f) value: 0.82 (Silica gel; methylenechloride/ethyl acetate=1:1)

(26) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3- 4-2-(ethoxycarbonyl)-1-phenyl-ethyl!phenyl!-imidazolidin-2-one

Melting point: 100°-102° C.; R_(f) value: 0.35 (Silica gel; methylenechloride/ethyl acetate=9:1)

(27) 1-(4-cyanobutyl)-3- 4-2-(methoxycarbonyl)ethyl!phenyl!imidazolidin-2-one

Melting point: 99°-101° C.; R_(f) value: 0.48 (Silica gel; ethylacetate/cyclohexane=7:3)

(28) 1- 2-(1-tert.butyloxycarbonyl-3-pyrrolidinyl)ethyl-3- 4-2-(methoxycarbonyl)ethyl!phenyl!-imidazolidin-2-one

Melting point: 118°-119° C.; R_(f) value: 0.50 (Silica gel; ethylacetate/cyclohexane=7:3)

(29) 1- 2-(1-benzyl-1-azoniabicyclo 2.2.2!octan-4-yl)-ethyl!-3- 4-2-(methoxycarbonyl)ethyl!phenyl!-imidazolidin-2-one chloride

R_(f) value: 0.16 (Silica gel; methylene chloride/methanol=9:1)

EXAMPLE 24

1-(trans-4-Carboxycyclohexyl)-3-4-(4-cyano-4-piperidinyl)-phenyl!-imidazolidin-2-one

To 1.4 g 1- 4-(4-cyano-1-trifluoroacetyl-4-piperidinyl)phenyl!-3-trans-4-(methoxycarbonyl)cyclohexyl!- imidazolidin-2-one in 25 ml oftetrahydrofuran and 6 ml of water are added 2.8 ml of 2N sodiumhydroxide solution and the mixture is stirred overnight. 5.6 ml of INhydrochloric acid are added, the tetrahydrofuran is evaporated off andthe residue is adjusted to a pH of 7.0 using sodium hydroxide solution.It is stirred in an ice bath for 1 hour, the product is suctionfiltered, washed with a little ice water and with acetone and thendried.

Yield: 1.0 g (91 % of theory), R_(f) value: 0.61 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Mass spectrum: M⁺ =396

The following compounds are obtained analogously to Example 24:

(1) 1-(4-carboxybutyl)-3-4-(4-cyano-4-piperidinyl)-phenyl!-imidazolidin-2-one

R_(f) value: 0.62 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Mass spectrum: M⁺ =370

(2) 1-(trans-4-carboxycyclohexyl)-3-4-(4-methyl-4-piperidinyl)phenyl!-imidazolidin-2-one

R_(f) value: 0.58 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Mass spectrum: M⁺ =385

(3) 1-4-(1-aza-4-cycloheptyl)phenyl!-3-(trans-4-carboxycyclohexyl)-imidazolidin-2-one

(4) 1-(4-carboxybicyclo 2.2.2!octan-1-yl)-3-4-(4-piperidinyl)phenyl!-imidazolidin-2-one

(5) 4-(trans-4-carboxycyclohexyl)-2-4-(4-piperidinyl)-phenyl!-4H-1,2,4-triazol-3-one×1.1 H₂ O

Melting point: >220° C.; R_(f) value: 0.59 (Reversed Phase Silica gel;methanol/5% aqueous saline solution=6:4); Calculated: C 61.55 H 7.28 N14.36; Found: 61.88 7.28 14.06

(6) 4-(trans-4-carboxycyclohexyl)-2-4-(4-piperidinyl)phenyl!-5-methyl-4H-1,2,4-triazol-3-one×H₂ O

Melting point: >220° C.; R_(f) value: 0.54 (Reversed Phase Silica gel;methanol/5% aqueous saline solution=6:4); Calculated: C 62.67 H 7.51 N13.92; Found: 62.85 7.73 12.65

(7) 1-(trans-4-carboxycyclohexyl)-3-4-(4-piperidinyl)phenyl!-3H-imidazol-2-one×1.3 H₂ O

R_(f) value: 0.58 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 64.20 H 7.59 N 10.69; Found: 64.13 7.5610.78

(8) 1-(trans-4-carboxycyclohexyl)-3-4-(4-piperidinyl)phenyl!-imidazolidin-2-one×0.2 H₂ O

Melting point: 327°-330° C. (decomp.); Calculated: C 67.25 H 7.90 N11.20; Found: 67.19 7.95 11.50

EXAMPLE 25

1-4-(4-Aminocarbonyl-4-piperidinyl)phenyl!-3-(trans-4-carboxycyclohexyl)-imidazolidin-2-one×0.8H₂ SO₄

200 mg of 1-(trans-4-carboxycyclohexyl)-3-4-(4-cyano-4-piperidinyl)phenyl!-imidazolidin-2-one are stirred with 2ml of 85% sulphuric acid for 4 days at ambient temperature. Water isadded, with cooling, the precipitate is suction filtered, washed withice water and dried at 90° C. in vacuo.

Yield: 154 mg (54 % of theory), R_(f) value: 0.65 (Reversed Phase Silicagel; methanol/5% aqueous saline solution 6:4); Calculated: C 53.60 H6.46 N 11.36 S 5.20; Found: 53.68 6.76 11.23 5.89; Mass spectrum: (M+H)⁺=415

EXAMPLE 26

1- 4-(2-Carboxyethyl)phenyl!-3-2-(4-quinuclidinyl)ethyl!-imidazolidin-2-one-hydrochloride

Hydogen chloride is passed over a mixture of 1.05 g of 1- 4-2-(methoxycarbonyl)-ethyl!phenyl!-3-2-(4-quinuclidinyl)ethyl!-imidazolidin-2-one×BH₃ and 1 ml of tetramethylorthocarbonate in 35 ml of methanol, with stirring. The mixture isstirred at ambient temperature for 21/2 days, then evaporated down andthe residue is mixed with 10 ml of semi-concentrated hydrochloric acid.It is heated over a steam bath for three hours, cooled and evaporated todryness. The residue is stirred with acetone, suction filtered, washedwith acetone and ether and dried at 100° C.

Yield: 0.90 g (84 % of theory), Melting point: >250° C.; R_(f) value:0.49 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 61.83 H 7.41 N 10.30 Cl 8.69; Found: 61.567.34 10.38 8.42

The following compounds are obtained analogously to Example 26:

(1) 1- 2-(1-azabicyclo 2.2.1!heptan-4-yl)ethyl!-3-4-(2-carboxyethyl)phenyl!-imidazolidin-2-one-hydrochloride

(2) 1-(trans-4-carboxycyclohexyl)-3-4-(4-quinuclidinyl)phenyl!-imidazolidin-2-one-hydrochloride

EXAMPLE 27

4- trans-4-(Methoxycarbonyl)cyclohexyl!-2-4-(1-trifluoroacetyl-4-piperidinyl)phenyl!-5-methyl-4H-1.2.4-triazol-3-one

8.0 g of 4-(4-iodophenyl)-1-trifluoroacetylpiperidine (approximately 90tstrength), 4,5 g of 4-trans-4-(methoxycarbonyl)cyclohexyl!-5-methyl-4H-1,2,4-triazol-3-one,5.19 g of potassium carbonate, 0.59 ml of tris-2-(2-methoxyethoxy)ethyl!-amine, 0.42 g of copper(I)-chloride, 0.42 g ofcopper(I)-iodide and 80 ml of N-methyl-pyrrolidinone are stirred for 1hour at 170° C. under nitrogen. The mixture is cooled, suction filteredand washed with dimethylformamide. The filtrate is added to a silica gelcolumn and eluted with cyclohexane/ethyl acetate (1:1). The productfractions are evaporated down and the residue is stirred with waterovernight. The precipitate is suction filtered and dried at 100° C. invacuo.

Yield: 650 mg (7 %. of theory), R_(f) value: 0.30 (Silica gel;cyclohexane/ethyl acetate=1:1)

The following compound is obtained analogously to Example 27:

(1) 4- trans-4-(methoxycarbonyl)cyclohexyl!-2-4-(1-trifluoroacetyl-4-piperidinyl)phenyl!-4H-1,2,4-triazol-3-one

Melting point: 184°-186° C.; R_(f) value: 0.26 (Silica gel;cyclohexane/ethyl acetate=1:1)

EXAMPLE 28

1- trans-4-(5-Indanyloxycarbonyl)cyclohexyl!-3- 4-(1-benzyloxycarbonyl-4-piperidinyl)phenyl!-imidazolidin-2-one

1.5 g of 1-(trans-4-carboxycyclohexyl)-3-4-(1-benzyloxycarbonyl-4-piperidinyl) phenyl!-imidazolidin-2-one, 1.3 mlof thionylchloride and one drop of dimethylformamide are stirred for 2hours at ambient temperature. Then the mixture is evaporated to dryness,the residue is dissolved in 5 ml of methylenechloride and combined,whilst cooling with ice, with a solution of 0.4 g of 5-indanole, aspatula tip of 4-dimethylaminopyridine and 0.7 ml of triethylamine in 5ml of methylenechloride. After 5 hours' stirring at ambient temperaturea further 0.8 g of 5-indanole and 2.1 ml of triethylamine are added andthe mixture is stirred overnight. The reaction mixture is diluted with50 ml of methylenechloride and extracted three times with water. Theorganic phase is separated off, dried and evaporated down. The residueis purified by chromatography over a silica gel column withmethylenechloride/ethyl acetate/cyclohexane (1:1:1).

Yield: 1.57 g (85% of theory), Melting point: 172°-174° C.; R_(f) value:0.40 (Silica gel; cyclohexane/ethyl acetate/methylene chloride=2:1:1)

The following compound is obtained analogously to Example 28:

(1) 1- trans-4-(5-indanyloxycarbonyl)cyclohexyl!-3-4-(1-benzyloxycarbonyl-4-cyano-4-piperidinyl)phenyl!imidazolidin-2-one

Melting point: 194°-196° C.; R_(f) value: 0.27 (Silica gel;cyclohexane/ethyl acetate/methylene chloride=2:1:1)

EXAMPLE 29

1- 4- 2-(O-Ethylphosphono)ethyl!phenyl!-3-2-(1-tert.butyloxvcarbonyl-4-pineridinvl)ethyl!-imidazolidin-2-one

2,0 g of 1- 4- 2-(O,O'-diethylphosphono)ethyl!phenyl!-3-2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!imidazolidin-2-one and0.56 g of sodium iodide are refluxed for 4 days in 20 ml ofmethylethylketone. The mixture is cooled, the solid matter is suctionfiltered, washed with methylethylketone and dried. The solid matter isdissolved in 15 ml of water and the solution is mixed with 10% potassiumhydrogen sulphate solution until a pH of 2 is obtained. The mixture iscooled in an ice bath, the precipitate is suction filtered, washed withice water and dried.

Yield: 1.1 g (58 % of theory), R_(f) value: 0.16 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4)

EXAMPLE 30

1- 4-(2-Carboxyethyl)phenyl!-3-2-(4-piperidinyl)ethyl!-4-methyl-imidazolidin-2-one×1.1 HCl×x 0.2 H₂ O

260 mg of 1- 4- 2-(methoxycarbonyl)ethyl)phenyl!-3-2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-4-methyl-imidazolidin-2-oneare heated to 90° C. with 2.2 ml of 3N hydrochloric acid for 6.5 hours.The reaction mixture is evaporated down, the residue is twice evaporateddown with toluene and then triturated with acetone. The solid matter issuction filtered, washed with acetone and diethylether and dried at 60°C.

Yield: 200 mg (90 % of theory), Melting point: 180°-183° C.; R_(f)value: 0.46 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Calculated: C 59.58 H 7.63 N 10.42 Cl 9.67; Found: 59.497.76 10.38 9.64

The following compounds are obtained analogously to Example 30:

(1) 1-(1-carboxymethyl-5-indanyl)-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride

(2) 1- 4-(2-carboxyethyl)phenyl!-3-methyl-4-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride

(3) 1- 4-(2-carboxy-1-phenyl-ethyl)phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride

R_(f) value: 0.43 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(4) 1- trans-4- (carboxymethyl)oxy!cyclohexyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride×0.3 H₂ O

Melting point: 207°-209° C. (decomp.); R_(f) value: 0.64 (Reversed PhaseSilica gel; methanol/5% aqueous saline solution=6:4); Calculated: C54.69 H 8.31 N 10.63 Cl 8.97; Found: 54.39 8.21 10.63 9.33

(5) 1- 4-(2-carboxyethyl)-2-methyl-phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-on-hydrochloride

R_(f) value: 0.57 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4); Mass spectrum: M⁺ =359

(6) 1- 4-(2-carboxyethyl)-3-chlorophenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride

(7) 1-(2-carboxy-1,2,3,4-tetrahydro-6-naphthyl)-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride

(8) 1- 4-(2-carboxyethyl)-2-fluorophenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride×0.5 H₂ O

Melting point: 198°-200° C.; R_(f) value: 0.58 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 55.80 H6.90 N 10.27 Cl 8.67; Found: 55.86 6.68 10.56 9.01

(9) 1- 4-(2-carboxyethyl)-2-trifluoronethyl-phenyl!-3-2-(4-piperidinyl)ethyl!-iiuidazolidin-2-one-hydrochloride

R_(f) value: 0.50 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(10) 1-(trans-4-carboxycyclohexyl)-3- 4-(2-aminoethyl)oxy!-phenyl!-imidazolidin-2-one-hydrochloride

(11) 1- 4-(2-carboxyethyl)phenyl!-3-methyl-4-(4-piperidinyl)oxymethyl!-imidazolidin-2-one-hydrochloride

(12) 1-4-(2-carboxyethyl)phenyl!-3-(2-(2-oxo-1-piperazinyl)-ethyl!-imidazolidin-2-one-hydrochloride

(13) 1- 4-(2-carboxyethyl)phenyl!-3-2-(3-pyrrolidinyl)ethyl!-imidazolidin-2-one-hydrochloride×0.25 H₂ O

Melting point: 200°-203° C.; R_(f) value: 0.57 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 58.06 H7.17 N 11.28 Cl 9.52; Found: 57.97 7.12 11.28 9.73

(14) 1- 4-(2-carboxyethyl)phenyl!-3-3-(3-piperidinyl)propyl!-imidazolidin-2-one-hydrochloride

(15) 1- 4-(2-carboxyethenyl)phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride×1 H₂ O

Melting point: 307°-310° C. (decomp.); R_(f) value: 0.50 (Reversed PhaseSilica gel; tetrahydrofuran/water=5:4); Calculated: C 57.35 H 7.09 N10.56; Found: 57.49 7.15 10.60; Mass spectrum: M⁺ =343

(16) 1- 4-(2-carboxyethyl)-2-cyano-phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-hydrochloride

R_(f) value: 0.71 (Reversed Phase Silica gel; methanol/5% aqueous salinesolution=6:4)

(17) 1- 1-(2-carboxyethyl)-piperidin-4-yl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one-dihydrochloride

EXAMPLE 31

1- 4-(2-Phosphonoethyl)phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one×1.5 H₂ O

450 mg of 1- 4- 2-(O-ethyl-phosphono)ethyl!phenyl!-3-2-(4-piperidinyl)ethyl!-imidazolidin-2-one×0.9 HCl×1.1 H₂ O, 22.5 ml ofmethylenechloride and 0.9 ml of bromotrimethylsilane are refluxed for 3hours. The mixture is evaporated to dryness, the residue obtained isdissolved in 15 ml of water and adjusted to pH 7 with 1N sodiumhydroxide solution. The precipitate obtained is suction filtered, washedwith water and dried.

Yield: 260 mg (70 % of theory), R_(f) value: 0.58 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 52.93 H7.65 N 10.28; Found: 52.80 7.48 10.34

EXAMPLE 32

1-(2-Cyano-1,2,3,4-tetrahydro-6-naphthyl)-3-trans-4-(methoxycarbonyl)cyclohexyl!-3H-imidazol-2-one

2.5 g ofN-(2-cyano-1,2,3,4-tetrahydro-6-naphthyl)-N'-(2,2-diethoxyethyl)-N'-trans-4-(methoxycarbonyl)cyclohexyl!- urea are dissolved in 20 mltrifluoroacetic acid and refluxed for 2.5 hours. Then, the mixture iscooled, evaporated down to dryness and the residue is taken up in 75 mlwater and neutralized with 2N sodium hydroxide solution. The solidmaterial obtained is suction filtered, washed with water, dried andpurified by chromatography over a silica gel column with ethylacetate/methylene chloride/cyclohexane (1:1:1).

Yield: 1.4 g (70% of theory); Melting point: 175°-176° C.; R_(f) value:0.34 (Silica gel; ethyl acetate/cyclohexane=3:2)

The following compounds are obtained analogously to Example 32:

(1) 1- 2-(methoxycarbonyl)-6-naphthyl!-3-2-(4-piperidinyl)ethyl!-3H-imidazol-2-one-trifluoroacetate

With simultaneous cleavage of the N-tert.butyloxy-carbonyl protectinggroup.

Melting point: 148°-151° C.; R_(f) value: 0.38 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Calculated: C 58.41 H5.31 N 8.51; Found: 58.47 5.39 8.51

(2) 1- 2-(methoxycarbonyl)-1,2,3,4-tetrahydro-6-naphthyl!-3-2-(4-piperidinyl)ethyl!-3H-imidazol-2-one

With simultaneous cleavage of the N-tert.butyloxy-carbonyl protectinggroup; isolation of the base

Melting point: 116°-118° C.; R_(f) value: 0.50 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4)

(3) 1-(trans-4-(methoxycarbonyl)cyclohexyl!-3-4-(4-quinuclidinyl)phenyl!-3H-imidazol-2-one

Isolation of the base

Melting point: 223°-225° C.; R_(f) value: 0.47 (Reversed Phase Silicagel; methanol/5% aqueous saline solution=6:4); Mass spectrum: M⁺ =409

(4) 1- trans-4-(methoxycarbonyl)cyclohexyl!-3-4-(4-methyl-1-trifluoroacetyl-4-piperidinyl)phenyl!-3H-imidazol-2-one

Melting point: 182°-184° C.; R_(f) value: 0.44 (Silica gel; methylenechloride/ethyl acetate=4:1)

(5) 1-(4-cyano-bicyclo 2.2.2!octan-1-yl)-3- 4-2-(methoxycarbonyl)ethyl!phenyl!-imidazolidin-2-one

Melting point: 195°-197° C.; R_(f) value: 0.68 (Silica gel; methylenechloride/ethyl acetate=4:1)

(6) 1- 2-(1-benzyl-l-azoniabicyclo 2.2.2!octan-4-yl)ethyl!-3- -4-2-(methoxycarbonyl)ethyl!phenyl!-3H-imidazol-2-one-chloride

R_(f) value: 0.19 (Silica gel; methylene chloride/methanol=100:7)

EXAMPLE 33

1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3- 4-2-(methoxycarbonyl)ethyl!-2-fluoro-phenyl!-imidazolidin-2-one

2.0 g of 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)-ethyl!-3- 4-2-(methoxycarbonyl)ethenyl!-2-fluoro-phenyl!-imidazolidin-2-one ishydrogenated with 0.5 g of 10% palladium on charcoal in 20 ml of ethylacetate for 15 minutes at ambient temperature and a hydrogen pressure of50 psi. The mixture is suction filtered and the filtrate is evaporatedto dryness.

Yield: 2.0 g (100% of theory); R_(f) value: 0.65 (Silica gel; ethylacetate/cyclohexane=3:1)

The following compounds are obtained analogously to Example 33:

(1) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl!-3- 4-2-(methoxycarbonyl)ethyl!-2-trifluoromethyl-phenyl!-imidazolidin-2-one

R_(f) value: 0.50 (Silica gel; ethyl acetate/cyclohexane=2:1)

(2) 1- 2-(1-tert.butyloxycarbonyl-4-piperidinyl)-ethyl!-3- 4-2-(methoxycarbonyl)ethyl!-2-methyl-phenyl!-imidazolidin-2-one

R_(f) value: 0.60 (Silica gel; ethyl acetate/cyclohexane=2:1)

EXAMPLE 34

1- 4- (Cyanomethyl)oxy!phenyl!-3-trans-4-(methoxycarbonyl)cyclohexyl!-imidazolidin-2-one

270 mg of potassium carbonate and 210 mg of bromoacetonitrile are addedto a solution of 500 mg of 1-(4-hydroxyphenyl)-3-trans-4-(methoxycarbonyl)-cyclohexyl!-imidazolidin-2-one in 3 ml ofdimethyl-formamide and heated for 5.5 hours at 60° C. The mixture isevaporated down. The residue is taken up in water, neutralized with 2Ncitric acid and extracted 4 times with ethyl acetate. The combinedorganic phases are washed with water, dried and evaporated down invacuo. The residue is purified by chromatography over a silica gelcolumn with methylene chloride/ethyl acetate (100:8).

Yield: 370 mg (65% of theory); Melting point: 136°-138° C.; R_(f) value:0.33 (Silica gel; ethyl acetate/cyclohexane=1:1)

EXAMPLE 35

Dry Ampoule Containing 2.5 mg of Active Substance per 1 ml

    ______________________________________    Composition:    ______________________________________    Active substance        2.5    mg    Mannitol                50.0   mg    Water for injections ad 1.0    ml    ______________________________________

Preparation:

Active substance and mannitol are dissolved in water. After transferringthe solution to the ampoule, it is freeze-dried.

At the point of use, the solution is made up with water for injections.

EXAMPLE 36

Dry Ampoule Containing 35 mg of Active Substance per 2 ml

    ______________________________________    Composition:    ______________________________________    Active substance        35.0   mg    Mannitol                100.0  mg    Water for injections ad 2.0    ml    ______________________________________

Preparation: active substance and mannitol are dissolved in water. Aftertransferring the solution to the ampoule, it is freeze-dried.

At the point of use, the solution is made up with water for injections.

EXAMPLE 37

Tablet Containing 50 mg of Active Substance

    ______________________________________    Composition:    ______________________________________    (1) Active substance 50.0 mg    (2) Lactose          98.0 mg    (3) Corn starch      50.0 mg    (4) Polyvinylpyrrolidone                         15.0 mg    (5) Magnesium stearate                         2.0 mg                         215.0 mg    ______________________________________

Preparation: (1), (2) and (3) are mixed together and granulated with anaqueous solution of (4). (5) is mixed with the dried granules. From thismixture, compressed tablets are produced, biplanar, facetted on bothsides and notched on one side. Diameter of tablets: 9 mm.

EXAMPLE 38

Tablet Containing 350 mg of Active Substance

    ______________________________________    Composition:    ______________________________________    (1) Active substance 350.0 mg    (2) Lactose          136.0 mg    (3) Corn starch      80.0 mg    (4) Polyvinylpyrrolidone                         30.0 mg    (5) Magnesium stearate                         4.0 mg                         600.0 mg    ______________________________________

Preparation: (1), (2) and (3) are mixed together and granulated with anaqueous solution of (4). (5) is mixed with the dried granules. From thismixture, compressed tablets are produced, biplanar, facetted on bothsides and notched on one side. Diameter of tablets: 12 mm.

EXAMPLE 39

Capsule Containing 50 mg of Active Substance

    ______________________________________    Composition:    ______________________________________    (1) Active substance 50.0 mg    (2) Dried corn starch                         58.0 mg    (3) Powdered lactose 50.0 mg    (4) Magnesium stearate                         2.0 mg                         160.0 mg    ______________________________________

Preparation: (1) is triturated with (3). This triturate is added to themixture of (2) and (4), with thorough mixing.

This powdered mixture is packed into size 3 hard gelatin oblong capsulesin a capsule filling machine.

EXAMPLE 40

Capsule Containing 350 mg of Active Substance

    ______________________________________    Composition:    ______________________________________    (1) Active substance 350.0 mg    (2) Dried corn starch                         46.0 mg    (3) Powdered lactose 30.0 mg    (4) Magnesium stearate                         4.0 mg                         430.0 mg    ______________________________________

Preparation: (1) is triturated with (3). This triturate is added to themixture of (2) and (4), with thorough mixing.

This powdered mixture is packed into size 0 hard gelatin oblong capsulesin a capsule filling machine.

What is claimed is:
 1. A cyclic urea derivative of formula ##STR17##wherein X is a carbonyl group;Y is a --CH₂ CH₂ -- group optionallysubstituted by R_(c) or by R_(c) and R_(d), whereinR_(c) is a hydrogenatom or a methyl, trifluoromethyl or phenyl group, and R_(d) is ahydrogen atom or a methyl group; R_(a) is a group of the formula

    A--B--C--

(wherein A together with B is a piperidinyl group wherein the hydrogenatom in the 1-position together with a hydrogen atom in the 2-positionis replaced by a straight-chained C₃₋₄ -alkylene group, or a piperidinylgroup in which the hydrogen atom in the 1-position together with ahydrogen atom in the 3-position is replaced by a straight-chained C₂₋₄-alkylene group, or a piperidinyl group in which the hydrogen atom inthe 1-position together with a hydrogen atom in the 4-position isreplaced by a straight-chained C₁₋₃ -alkylene group, whilst a 4-positionbound methylene group of an ethylene chain may be replaced by ahydroxymethylene or carbonyl group; and C is a C₁₋₄ -alkylene group)R_(b) is a group of the formula

    F--E--D--

(wherein D is a 1,3- or 1,4-phenylene group optionally substituted by afluorine or chlorine atom or by a methyl, trifluoromethyl or cyanogroup, or a 1,4-cyclohexylene group; E is a C₁₋₄ -alkylene group whichmay be substituted by a C₁₋₄ -alkyl group, by a phenyl group or by aC₁₋₄ -alkylsulphonylamino group; F is a carbonyl group which issubstituted by a hydroxy group, by a C₁₋₅ -alkoxy group, by aphenylalkoxy group having 1 to 3 carbon atoms in the alkoxy moiety or byan R₇ O-- group, whereinR₇ is a C₅₋₇ -cycloalkyl group or acyclohexylmethyl or indanyl group, or F is an R₈ CO--O--CHR₉ --O--CO--group, whereinR₈ is a cycloalkyloxy group having 5 to 7 carbon atoms inthe cycloalkyl moiety, an alkyl or alkoxy group each having 1 to 4carbon atoms, and R₉ is a hydrogen atom or a methyl group) and theshortest distance between the group F and the furthest removed nitrogenatom of the groups A--B--C-- amounts to at least 11 bonds; a tautomerthereof, a stereoisomer thereof or a salt thereof.
 2. The cyclic ureaderivative of formula I as claimed in claim 1, whereinA together with Bis a piperidinyl group wherein the hydrogen atom in the 1-positiontogether with a hydrogen atom in the 4-position is replaced by astraight-chained C₁₋₃ -akylene group, whilst the 4-position boundmethylene group of an ethylene chain may be replaced by ahydroxymethylene or carbonyl group; a tautomer thereof, a stereoisomerthereof or a salt thereof.
 3. The cyclic urea derivative of formula Iaccording to claim 1 whereinX is a carbonyl group; Y is a --CH₂ CH₂ --group optionally substituted by R_(c) or by R_(c) and R_(d),whereinR_(c) is a hydrogen atom or a methyl, trifluoromethyl or phenylgroup, and R_(d) is a hydrogen atom or a methyl group; R_(a) is a groupof the formula

    A--B--C--

(wherein A together with B is a piperidinyl group wherein the hydrogenatom in the 1-position together with a hydrogen atom in the 4-positionis replaced by methylene, ethylene or 1,3-propylene group; and C is a--CH₂ CH₂ -- group) and R_(b) is a group of the formula

    F--E--D--

(wherein D is a 1,4-phenylene group optionally substituted by a fluorineatom or by a methyl, trifluoromethyl or cyano group, or a1,4-cyclohexylene group; E is a straight-chained C₂₋₄ -alkylene groupoptionally substituted by a C₁₋₄ -alkyl group, by a phenyl group or by aC₁₋₄ -alkylsulphonylamino group; and F is a carbonyl group which issubstituted by a hydroxy group, by a C₁₋₄ -alkoxy group or by an R₇ O--group, wherein R₇ is a cyclopentyl, cyclohexyl or 5-indanyl group, or Fis an R₈ CO--O--CHR₉ --O--CO-- group, whereinR₈ is a tert.butyl, ethoxyor cyclohexyloxy group and R₉ is a hydrogen atom or a methyl group) andthe shortest distance between the group F and the furthest removednitrogen atom of the groups A--B--C-- amounts to at least 11 bonds; atautomer thereof, a stereoisomer thereof or a salt thereof.
 4. Thecyclic urea derivative of formula I according to claim 1 whereinX is acarbonyl group; Y is a --CH₂ CH₂ -- group optionally substituted byR_(c) or by R_(c) and R_(d), whereinR_(c) is a hydrogen atom or amethyl, trifluoromethyl or phenyl group, and R_(d) is a hydrogen atom ora methyl group; R_(a) is a group of the formula

    A--B--C--

(wherein A together with B is a piperidinyl group wherein the hydrogenatom in the 1-position together with a hydrogen atom in the 4-positionis replaced by methylene or ethylene group; and C is a --CH₂ CH₂ --group) and R_(b) is a group of the formula

    F--E--D--

(wherein D is a 1,4-phenylene group optionally substituted by a fluorineatom or by a methyl, trifluoromethyl or cyano group, or a1,4-cyclohexylene group; E is a straight-chained C₂₋₄ -alkylene groupoptionally substituted by a C₁₋₄ -alkyl group, by a phenyl group or by aC₁₋₄ -alkylsulphonylamino group; and F is a carbonyl group which issubstituted by a hydroxy group, by a C₁₋₄ -alkoxy group or by an R₇ O--group, whereinR₇ is a cyclopentyl, cyclohexyl or 5-indanyl group, or Fis an R₈ CO--O--CHR₉ --O--CO-- group, whereinR₈ is a tert.butyl, ethoxyor cyclohexyloxy group and R₉ is a hydrogen atom or a methyl group) andthe shortest distance between the group F and the furthest removednitrogen atom of the groups A--B--C-- amounts to at least 11 bonds; atautomer thereof, a stereoisomer thereof or a salt thereof.
 5. Thecyclic urea derivative of formula I according to claim 1 whereinX is acarbonyl group; Y is a --CH₂ CH₂ -- group optionally substituted byR_(c) or by R_(c) and R_(d), whereinR_(c) is a hydrogen atom or amethyl, trifluoromethyl or phenyl group, and R_(d) is a hydrogen atom ora methyl group; R_(a) is a group of the formula

    A--B--C--

(wherein A together with B is a 4-quinuclidinyl group, and C is a --CH₂CH₂ -- group) and R_(b) is a group of the formula

    F--E--D--

(wherein D is a 1,4-phenylene or 1,4-cyclohexylene group; E is anethylene group; and F is a carbonyl group which is substituted by ahydroxy group, by a C₁₋₄ -alkoxy group or by an R₇ O-- group, wherein R₇is a cyclopentyl or cyclohexyl group; and the shortest distance betweenthe group F and the furthest removed nitrogen atom of the groupsA--B--C-- amounts to at least 11 bonds; a tautomer thereof, astereoisomer thereof or a salt thereof.
 6. The cyclic urea derivative offormula I according to claim 1 selected from the group:(a) 1-4-(2-carboxyethyl)phenyl!-3-2-(4-quinuclidinyl)ethyl!-imidazolidin-2-one, (b) 1-(trans-4-(2-carboxyethyl)-cyclohexyl!-3-2-(4-quinuclidinyl)ethyl!-imidazolidin-2-one, and (c) 3-4-(2-carboxyethyl)phenyl!-1- 2-(1-azabicyclo 2.2.1!heptan-4-yl)ethyl!-imidazolidin2-one, or a C₁₋₃ -alkyl ester thereofor a salt thereof.
 7. 1- 4-(2-carboxyethyl)phenyl!-3-2-(4-quinuclidinyl)ethyl!-imidazolidin-2-one, or the ethyl ester or asalt thereof.